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60 gesichtete, geschützte Fragmente: Plagiat

[1.] Mmu/Fragment 071 20 - Diskussion
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Some smaller or atypical deletions have been reported but there is no evidence for specific genotype–phenotype correlations. It has been argued that the 1.5Mb deletions contain all key genes responsible for the syndrome (Carlson et al., 1997).

The phenotypic spectrum encompasses several previously described syndromes including DiGeorge, velocardiofacial and conotruncal anomaly face syndromes as well as some individuals with other conditions such as Cayler cardiofacial syndrome. The phenotypic expression of the 22q11.2DS is known to be highly variable and ranges from a severe life-threatening condition to affected individuals with few associated features (Bassett et al. 2005; Kobrynski and Sullivan 2007; Ryan et al. 1997). Abnormal development of the pharyngeal arches and pharyngeal pouches [gives rise to the cardinal physical manifestations of the syndrome: conotruncal anomaly, hypocalcemia due to dysfunctional parathyroid glands, palatal abnormalities and paediatric immunodeficiency that may be secondary to hypo/aplasia of the thymus (Lindsay et al. 2001; Scambler 2000).]


1. Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet Part A. 2005; 138:307–313.

6. Carlson C, Sirotkin H, Pandita R, Goldberg R, McKie J, et al: Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J Hum Genet 61: 620–629 (1997).

17. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007; 370:1443–1452.

24. Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, Schuffenhauer S, Oechsler H,Belohradsky B, Prieur M, Aurias A, Raymond FL, Clayton-Smith J, Hatchwell E, McKeown C, Beemer FA, Dallapiccola B, Novelli G, Hurst JA, Ignatius J, Green AJ, Winter RM, Brueton L, Brondum-Nielsen K, Scambler PJ, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997; 34:798–804.

The phenotypic spectrum encompasses several previously described syndromes including DiGeorge, velocardiofacial and conotruncal anomaly face syndromes as well as some individuals with other conditions such as Cayler cardiofacial syndrome. The phenotypic expression of the 22q11.2DS is known to be highly variable and ranges from a severe life-threatening condition to

[page 2]

affected individuals with few associated features (Bassett et al. 2005; Kobrynski and Sullivan 2007; Ryan et al. 1997). Abnormal development of the pharyngeal arches and pharyngeal pouches gives rise to the cardinal physical manifestations of the syndrome: conotruncal anomaly, hypocalcemia due to dysfunctional parathyroid glands, palatal abnormalities and paediatric immunodeficiency that may be secondary to hypo/aplasia of the thymus (Lindsay et al. 2001; Scambler 2000).

[...]

Some smaller or atypical deletions have been reported but there is no evidence for specific genotype–phenotype correlations.


Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet Part A. 2005; 138:307–313. [PubMed: 16208694]

Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007; 370:1443–1452. [PubMed: 17950858]

Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, Schuffenhauer S, Oechsler H, Belohradsky B, Prieur M, Aurias A, Raymond FL, Clayton-Smith J, Hatchwell E, McKeown C, Beemer FA, Dallapiccola B, Novelli G, Hurst JA, Ignatius J, Green AJ, Winter RM, Brueton L, Brondum-Nielsen K, Scambler PJ, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997; 34:798–804. [PubMed: 9350810]

Shaikh TH, Kurahashi H, Saitta SC, O’Hare AM, Hu P, Roe BA, Driscoll DA, McDonald-McGinn DM, Zackai EH, Budarf ML, Emanuel BS. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet. 2000; 9:489–501. [PubMed: 10699172]

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[2.] Mmu/Fragment 071 03 - Diskussion
Bearbeitet: 7. February 2016, 14:57 Hindemith
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Introduction

Microdeletion of chromosome 22q11.2 or 22q11.2 deletion syndrome (22q11.2DS) (MIM#188400/#192430) is the most common human deletion syndrome with an estimated prevalence of 1 in 4,000 live births (Goodship 1998). Up to 93% of cases occurs [sic] de novo, whereas in the remaining 7% the deletion is found to be inherited from a parent.


11. Goodship J, Cross I, LiLing J, Wren C. A population study of chromosome 22q11 deletions in infancy. Arch Dis Child. 1998; 79:348–351.

Introduction

Microdeletion of chromosome 22q11.2 or 22q11.2 deletion syndrome (22q11.2DS) (MIM#188400/#192430) is the most common human deletion syndrome with an estimated prevalence of 1 in 4,000 live births (Goodship et al. 1998).

[page 2]

Up to 93% of cases occur de novo, whereas in the remaining 7% the deletion is found to be inherited from a parent.

Anmerkungen

The source is not given.

Goodship et al. (1998) does not contain the parallel text.

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[3.] Mmu/Fragment 034 12 - Diskussion
Bearbeitet: 7. February 2016, 14:56 Hindemith
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Multiplex Ligation-dependant Probe Amplification (MLPA) analysis

We used a distinct commercially available MLPA kit, the SALSA P036D subtelomeric primer set (MRC-Holland, Amsterdam, The Netherlands). This kit contains oligonucleotide primer sets specific for the amplification of selected loci in the subtelomeric regions of all chromosome arms, except for the acrocentric chromosomes 13, 14, 15, 21 and 22 that effectively lack a short arm. For the latter, the manufacturer has included in this kit primer sets specific for loci adjacent to the centromere in the long arm of the acrocentric chromosomes, referred to as the ‘acrocentric’ primer. This kit was previously validated in other laboratories (data not shown) on series of patients with known subtelomeric ultra conserved regions (UCRs) [29, 30]. The target loci of this kit represent known functional genes or protein coding sequences. Each experiment was carried out according to the manufacturer’s instructions.

Fluorescent in situ hybridization (FISH) analysis

Chromosomal preparations for the analysis were obtained according to standard techniques. FISH was performed with TelVision 9p and 17p probes (Vysis). Each experiment was carried out according to the manufacturer’s instructions.


[29] Ahn J W, Ogilvie C M, Welch A, Thomas H, Madula R, Hills A, Donaghue C, Mann K. (2007) Detection of subtelomere imbalance using MLPA: validation, development of an analysis protocol, and application in a diagnostic centre. BMC Med Genet 8:9

[30] Rooms L, Reyniers E, van Luijk R, Scheers S, Wauters J, Ceulemans B, Van Den Ende J, Van Bever Y, Kooy R F. (2004) Subtelomeric deletions detected in patients with idiopathic mental retardation using multiplex ligation-dependent probe amplification (MLPA). Hum Mutat 23:17-21

MATERIAL AND METHODS

Multiplex Ligation-dependant Probe Amplification (MLPA) analysis

We used a distinct commercially available MLPA kit, the SALSA P036D subtelomeric primer set (MRC-Holland, Amsterdam, The Netherlands). This kit contains oligonucleotide primer sets specific for the amplification of selected loci in the subtelomeric regions of all chromosome arms, except for the acrocentric chromosomes 13, 14, 15, 21 and 22 that effectively lack a short or p-arm. For the latter the manufacturer has included in this kit primer sets specific for loci adjacent to the centromere in the long arm of the acrocentric chromosomes, referred to as the ‘acrocentric’ primer. This kit was previously validated in other laboratories (data not shown) on series of patients with known subtelomeric UCRs [Ahn J et al. 2007, Kirchhoff et al. 2005, Rooms et al. 2004]. The target loci of this kit represent known functional genes or protein coding sequences.

[...]

FISH analysis

Chromosomal preparations for the analysis were obtained according to standard techniques. Fluorescent in situ hybridization (FISH) was performed with TelVision 9p and 17p probes (Vysis). Each experiment was carried out according to the manufacturer’s instructions.

Anmerkungen

Nothing has been marked as a citation.

The original text is part of an article which is included in Katzaki's thesis. Mmu was not one of the coauthors of this article. The references for Ahn J et al. 2007, Kirchhoff et al. 2005, Rooms et al. 2004 are all missing in Katzaki (2009).

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[4.] Mmu/Fragment 026 01 - Diskussion
Bearbeitet: 7. February 2016, 14:53 Hindemith
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Amplification products were identified and quantified by capillary electrophoresis on an ABI 310 genetic analyzer, using GENESCAN software (version 3.7) all from Applied Biosystems (Foster City, CA, USA). The peak areas of the PCR products were determined by GENOTYPER software (Applied Biosystems). A spreadsheet was developed in MicrosoftTM Excel in order to process the sample data efficiently. Data were normalized by dividing each probe’s peak area by the average peak area of the sample. This normalized peak pattern was divided by the average normalized peak pattern of all the samples in the same experiment (Koolen 2004).

36. Koolen, D.A., et al., Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA). J Med Genet, 2004. 41(12): p. 892-9.

Amplification products were identified and quantified by capillary electrophoresis on an ABI 310 genetic analyzer, using GENESCAN software (version 3.7) all from Applied Biosystems (Foster City, CA, USA). The peak areas of the PCR products were determined by GENOTYPER software (Applied Biosystems). A spreadsheet was developed in MicrosoftTM Excel in order to process the sample data efficiently. Data were normalized by dividing each probe’s peak area by the average peak area of the sample. This normalized peak pattern was divided by the average normalized peak pattern of all the samples in the same experiment. [96]

96. Koolen, D.A., et al., Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA). J Med Genet, 2004. 41(12): p. 892-9.

Anmerkungen
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[5.] Mmu/Fragment 025 01 - Diskussion
Bearbeitet: 7. February 2016, 14:52 Hindemith
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3.3 Real-time quantitative PCR

Some aCGH data were confirmed by Real-time Quantitative PCR experiments. To design adequate probes in different regions of the human genome, we used an TaqMan Gene Expression Assays by design which provides pre-designed primers-probe set for real-time PCR experiments (Applied Biosystems, https://products.appliedbiosystems.com). PCR was carried out using an ABI prism 7000 (Applied Biosystems) in a 96-well optical plate with a final reaction volume of 50 μl. A total of 100 ng (10 μl) was dispensed in each of the four sample wells for quadruplicate reactions. Thermal cycling conditions included a pre-run of 2 min at 50°C and 10 min at 95°C. Cycle conditions were 40 cycles at 95°C for 15 sec and 60°C for 1 min according to the TaqMan Universal PCR Protocol (ABI). The TaqMan Universal PCR Master Mix and Microamp reaction tubes were supplied by Applied Biosystems. The starting copy number of the unknown samples was determined using the comparative Ct method as previously described (Ariani 2004).

3.4 Multiplex Ligation-dependent Probe Amplification (MLPA)

MLPA analysis was performed according to the provider’s protocol with a specifically designed set of probes for testing critical regions in DiGeorge syndrome (SALSA P023 kit; MRC-Holland, Amsterdam, Netherlands; http://www.mrc-holland.com), 1p-deletion syndrome, Williams syndrome, Smith-Magenis syndrome, Miller-Dieker syndrome, DiGeorge syndrome, Prader-Willi syndrome, Alagille syndrome, Saethre-Chotzen syndrome, Sotos syndrome: (SALSA P064B MR1 kit) and subtelomere regions (SALSA P036D subtelomeric primer kit). The ligation products were amplified by PCR using the common primer set with the 6-FAM label distributed by the supplier. Briefly, 100 ng of genomic DNA was diluted with TE buffer to 5 μl, denatured at 98°C for 5 minutes and hybridized with SALSA Probe-mix at 60°C overnight. Ligase-65 mix was then added and ligation was performed at 54°C for 15 minutes. The ligase was successively inactivated by heat, 98°C for 5 minutes. PCR reaction was performed in a 50 μl volume. Primers, dNTP and polymerase were added and amplification was carried out for 35 cycles (30 seconds [at 95°C, 30 seconds at 60°C and 60 seconds at 72°C).]


2. Ariani, F., et al., Real-time quantitative PCR as a routine method for screening large rearrangements in Rett syndrome: Report of one case of MECP2 deletion and one case of MECP2 duplication. Hum Mutat, 2004. 24(2): p. 172-7.

3.3 Real-time quantitative PCR

Some aCGH data were confirmed by Real-time Quantitative PCR experiments. To design adequate probes in different regions of the human genome, we used an TaqMan Gene Expression Assays by design which provides pre-designed primers-probe set for real-time PCR experiments (Applied Biosystems, https://products.appliedbiosystems.com) PCR was carried out using an ABI prism 7000 (Applied Biosystems) in a 96-well optical plate with a final reaction volume of 50 μl. A total of 100 ng (10 μl) was dispensed in each of the four sample wells for quadruplicate reactions. Thermal cycling conditions included a prerun of 2 min at 50°C and 10 min at 95°C. Cycle conditions were 40 cycles at 95°C for 15 sec and 60°C for 1 min according to the TaqMan Universal PCR Protocol (ABI). The TaqMan Universal PCR Master Mix and Microamp reaction tubes were supplied by Applied Biosystems. The starting copy number of the unknown samples was determined using the comparative Ct method as previously described. [95]

[page 31:]

3.4 Multiplex Ligation-dependent Probe Amplification (MLPA)

MLPA analysis was performed according to the provider’s protocol with a specifically designed set of probes for testing critical regions in DiGeorge syndrome (SALSA P023 kit; MRC-Holland, Amsterdam, Netherlands; http://www.mrc-holland.com), 1p-deletion syndrome, Williams syndrome, Smith- Magenis syndrome, Miller-Dieker syndrome, DiGeorge syndrome, Prader-Willi syndrome, Alagille syndrome, Saethre-Chotzen syndrome, Sotos syndrome: (SALSA P064B MR1 kit) and subtelomere regions (SALSA P036D subtelomeric primer kit). The ligation products were amplified by PCR using the common primer set with the 6-FAM label distributed by the supplier. Briefly, 100 ng of genomic DNA was diluted with TE buffer to 5 μl, denatured at 98°C for 5 minutes and hybridized with SALSA Probe-mix at 60°C overnight. Ligase-65 mix was then added and ligation was performed at 54°C for 15 minutes. The ligase was successively inactivated by heat, 98°C for 5 minutes. PCR reaction was performed in a 50 μl volume. Primers, dNTP and polymerase were added and amplification was carried out for 35 cycles (30 seconds at 95°C, 30 seconds at 60°C and 60 seconds at 72°C).


95. Ariani, F., et al., Real-time quantitative PCR as a routine method for screening large rearrangements in Rett syndrome: Report of one case of MECP2 deletion and one case of MECP2 duplication. Hum Mutat, 2004. 24(2): p. 172-7.

Anmerkungen
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[6.] Mmu/Fragment 018 20 - Diskussion
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As clinical variability is not explained by differences in gene content within the deletion, allelic variation(s) in the non-deleted homologous region is considered a possible contributor to phenotypic variability. Most of the genes from the 22q11.2 deletion region are expressed in fetal and adult brain, thus are candidates for both the psychiatric phenotype of patients with 22q11.2 deletions and susceptibility to psychiatric disorders in the general population (Meechan et al. 2010).

19. Meechan DW, Maynard TM, Tucker ES, Lamantia AS. Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes. Int J Dev Neurosci. 2011 May;29(3):283-94.

As clinical variability is not explained by differences in gene content within the deletion, allelic variation(s) in the non-deleted homologous region is considered a possible contributor to phenotypic variability. [...]

[...]

Most of the genes from the 22q11.2 deletion region are expressed in fetal and adult brain, thus are candidates for both the psychiatric phenotype of patients with 22q11.2 deletions and susceptibility to psychiatric disorders in the general population (Meechan et al. 2010).


Meechan DW, Maynard TM, Tucker ES, Lamantia AS. Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes. Int J Dev Neurosci. 2010 in press.

Anmerkungen

The source is not given.

Meechan et al. (2011) does not contain the text.

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[7.] Mmu/Fragment 018 01 - Diskussion
Bearbeitet: 7. February 2016, 14:49 Hindemith
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Developmental delays and learning difficulties are very commonly associated, although severe intellectual disability is rare. Recurrent seizures are common and epilepsy may be present in about 5% of patients. Psychiatric conditions may be present in children and over 60% of patients develop treatable psychiatric disorders by adulthood (Bassett et al. 2005). In particular, due to the high frequency of schizophrenia in 22q11.2DS patients, the 22q11.2 region is considered to be one of the main schizophrenia susceptibility loci in humans (Bassett and Chow 2008; Insel 2010). Evidence from multiple studies indicates that about 1% of individuals with schizophrenia in the general population have 22q11.2 deletions (Bassett et al. 2010).

1. Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet Part A. 2005; 138:307–313.

2. Bassett AS, Chow EW. Schizophrenia and 22q11.2 deletion syndrome. Curr Psychiatry Rep. 2008; 10:148–157.

3. Bassett AS, Costain G, Fung WLA, Russell KJ, Pierce L, Kapadia R, Carter RF, Chow EW, Forsythe PJ. Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J Psychiatr Res. 2010; 44:1005–1009.

13. Insel TR. Rethinking schizophrenia. Nature. 2010; 468:187–193.

Developmental delays and learning difficulties are very commonly associated, although severe intellectual disability (termed mental retardation in the DSM diagnostic system) is rare. Recurrent seizures are common, especially those related to hypocalcemia, and epilepsy may be present in about 5% of patients. Psychiatric conditions may be present in children and over 60% of patients develop treatable psychiatric disorders by adulthood (Bassett et al. 2005). This risk is a major concern for families. In particular, due to the high frequency of schizophrenia in 22q11.2DS patients, the 22q11.2 region is considered to be one of the main schizophrenia susceptibility loci in humans (Bassett and Chow 2008; Insel 2010).

[page 5]

Evidence from multiple studies indicates that about 1% of individuals with schizophrenia in the general population have 22q11.2 deletions (Bassett et al. 2010).


Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet Part A. 2005; 138:307–313. [PubMed: 16208694]

Bassett AS, Chow EW. Schizophrenia and 22q11.2 deletion syndrome. Curr Psychiatry Rep. 2008; 10:148–157. [PubMed: 18474208]

Bassett AS, Costain G, Fung WLA, Russell KJ, Pierce L, Kapadia R, Carter RF, Chow EW, Forsythe PJ. Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J Psychiatr Res. 2010; 44:1005–1009. [PubMed: 20643418]

Insel TR. Rethinking schizophrenia. Nature. 2010; 468:187–193. [PubMed: 21068826]

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[8.] Mmu/Fragment 017 20 - Diskussion
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Microdeletion of chromosome 22q11.2 or 22q11.2 deletion syndrome (22q11.2DS) (MIM#188400/#192430) is the most common human deletion syndrome with an estimated prevalence of 1 in 4,000 live births (Goodship et al. 1998). The phenotypic spectrum encompasses several previously described syndromes including DiGeorge, velocardiofacial and conotruncal anomaly face syndromes as well as some individuals with other conditions such as Cayler cardiofacial syndrome. The phenotypic expression of the 22q11.2DS is known to be highly variable and ranges from a severe life-threatening condition to affected individuals with few associated features (Bassett et al. 2005; Kobrynski and Sullivan 2007; Ryan et al. 1997).

1. Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet Part A. 2005; 138:307–313.

11. Goodship J, Cross I, LiLing J, Wren C. A population study of chromosome 22q11 deletions in infancy. Arch Dis Child. 1998; 79:348–351.

17. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007; 370:1443–1452.

24. Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, Schuffenhauer S, Oechsler H,Belohradsky B, Prieur M, Aurias A, Raymond FL, Clayton-Smith J, Hatchwell E, McKeown C, Beemer FA, Dallapiccola B, Novelli G, Hurst JA, Ignatius J, Green AJ, Winter RM, Brueton L, Brondum-Nielsen K, Scambler PJ, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997; 34:798–804.

Microdeletion of chromosome 22q11.2 or 22q11.2 deletion syndrome (22q11.2DS) (MIM #188400/#192430) is the most common human deletion syndrome with an estimated prevalence of 1 in 4,000 live births (Goodship et al. 1998). The phenotypic spectrum encompasses several previously described syndromes including DiGeorge, velocardiofacial and conotruncal anomaly face syndromes as well as some individuals with other conditions such as Cayler cardiofacial syndrome. The phenotypic expression of the 22q11.2DS is known to be highly variable and ranges from a severe life-threatening condition to affected

[page 2]

individuals with few associated features (Bassett et al. 2005; Kobrynski and Sullivan 2007; Ryan et al. 1997).


Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet Part A. 2005; 138:307–313. [PubMed: 16208694]

Goodship J, Cross I, LiLing J, Wren C. A population study of chromosome 22q11 deletions in infancy. Arch Dis Child. 1998; 79:348–351. [PubMed: 9875047]

Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007; 370:1443–1452. [PubMed: 17950858]

Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, Schuffenhauer S, Oechsler H, Belohradsky B, Prieur M, Aurias A, Raymond FL, Clayton-Smith J, Hatchwell E, McKeown C, Beemer FA, Dallapiccola B, Novelli G, Hurst JA, Ignatius J, Green AJ, Winter RM, Brueton L, Brondum-Nielsen K, Scambler PJ, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997; 34:798–804. [PubMed: 9350810]

Anmerkungen

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See also: Mmu/Fragment 071 03

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[9.] Mmu/Fragment 004 07 - Diskussion
Bearbeitet: 6. February 2016, 20:32 Schumann
Erstellt: 17. December 2014, 00:31 (Graf Isolan)
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However, even high resolution karyotypes (Yunis 1976) are enable [sic] to detect many known microdeletion syndromes, which range from 3-5 Mb in size, and cannot detect smaller aberrations. In the 1990s the introduction of molecular cytogenetic techniques into the clinical laboratory setting represented a major advance in the ability to detect known syndromes and identify chromosomal rearrangements of unknown origin. Fluorescent in situ hybridization (FISH), which is the annealing of fluorescently labelled locus-specific probes to their complementary sequences in the genome, allowed for the detection of specific microdeletion syndromes (Trask 1991) (Fig.1b1-b2).

78. Trask BJ: Fluorescence in situ hybridization: applications in cytogenetics and gene mapping. Trends Genet 1991; 7: 149-154.

88. Yunis J: High resolution of human chromosomes. Science 1976; 191: 1268-1270.

[Page 15]

However, even high resolution karyotypes4 are unreliable for detecting many known microdeletion syndromes, which range from 3-5 Mb in size, and cannot detect smaller aberrations.

[Page 16]

In the 1990s the introduction of molecular cytogenetic techniques into the clinical laboratory setting represented a major advance in the ability to detect known syndromes and identify chromosomal rearrangements of unknown origin. Fluorescence in situ hybridization (FISH), which is the annealing of fluorescently labelled locus-specific probes to their complimentary [sic] sequences in the genome, allowed the detection of specific microdeletion syndromes (Fig. 2).5


4 Yunis J: High resolution of human chromosomes. Science 1976; 191: 1268-1270.

5 Trask BJ: Fluorescence in situ hybridization: applications in cytogenetics and gene mapping. Trends Genet 1991; 7: 149-154.

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Furthermore Walters et al; demonstrated that a 16p11.2 deletion give rise to a strongly-expressed obesity phenotype. Possible explanations include a direct causal relationship between obesity and developmental delay; the involvement of the same or related regulatory pathways; or different outcomes of the same set of behavioural disorders with complex pleiotropic effects and variable ages of onset and expressivities (Walters 2010).

84. Walters R. G. et al. A novel highly-penetrant form of obesity due to microdeletions on chromosome 16p11.2. Nature. 2010 February 4; 463(7281): 671–675

Possible explanations include a direct causal relationship between obesity and developmental delay, the involvement of the same or related regulatory pathways, or different outcomes of the same set of behavioural disorders with complex pleiotropic effects and variable ages of onset and expressivities.
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[The effective identification of such regions will likely require collaborative] efforts by multiple centres, in order to collect a sufficient numbers of patients carrying the same structural variant. A cohort of multiple individuals with a particular pathogenic variant will likely show at least some degree of phenotypic concordance even where penetrance is incomplete, making possible a more defined genotype-phenotype correlation. The effective identification of such regions will likely require collaborative efforts by multiple centers, such that sufficient numbers of patients carrying the same structural variant can be collected for study. [...] On the basis that multiple individuals with a particular pathogenic variant will likely show at least some degree of phenotypic concordance even where penetrance is incomplete, causality can also be inferred through the use of phenotype-genotype correlations.
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For the documentation an online version of the source has been used such that no page numbers could be documented.

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[Abnormal development of the pharyngeal arches and pharyngeal pouches] gives rise to the cardinal physical manifestations of the syndrome: conotruncal anomaly, hypocalcemia due to dysfunctional parathyroid glands, palatal abnormalities and paediatric immunodeficiency that may be secondary to hypo/aplasia of the thymus (Lindsay et al. 2001; Scambler 2000). Major heart defects are present in about 40% of cases while minor anomalies, e.g., of the aortic arch, may be identified only on cardiac ultrasonography. Overt cleft palate is rare, whereas submucous cleft palate associated with velopharyngeal insufficiency is characteristic of 22q11.2DS. In contrast, the facial features are considered a constant manifestation of the syndrome (Guyot et al. 2001), although the overall facial appearance is not always readily identifiable even to informed clinicians.

Developmental delays and learning difficulties are very commonly associated, although severe intellectual disability is rare. Recurrent seizures are common, especially those related to hypocalcemia, and epilepsy may be present in about 5% of patients. Psychiatric conditions may be present in children and over 60% of patients develop treatable psychiatric disorders by adulthood (Bassett et al. 2005). This risk is a major concern for families. In particular, due to the high frequency of schizophrenia in 22q11.2DS patients, the 22q11.2 region is considered to be one of the main schizophrenia susceptibility loci in humans (Bassett and Chow 2008; Insel 2010). Evidence from multiple studies indicates that about 1% of individuals with schizophrenia in the general population have 22q11.2 deletions (Basset et al, 2010). The commonly deleted region in 22q11.2 encompasses approximately 45 genes and most of them are expressed in fetal and adult brain, thus are candidates for both the psychiatric phenotype of patients with 22q11.2 deletions and susceptibility to psychiatric disorders in the general population (Meechan et al. 2010). As clinical variability is not explained by differences in gene content within the deletion, allelic variation(s) in the non-deleted homologous region is considered a possible contributor to phenotypic variability.


6. Bassett AS, et al. Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J Psychiatr Res. 2010; 44:1005–1009.

12. Guyot L, Dubuc M, Pujol J, Dutour O, Philip N. Craniofacial anthropometric analysis in patients with 22q11 microdeletion. Am J Med Genet. 2001; 100:1–8.

18. Lindsay EA, Baldini A. Recovery from arterial growth delay reduces penetrance of cardiovascular defects in mice deleted for the DiGeorge syndrome region. Hum Mol Genet. 2001; 10:997–1002.

19. Meechan DW, Maynard TM, Tucker ES, Lamantia AS. Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes. Int J Dev Neurosci. 2011 May;29(3):283-94.

26. Scambler PJ. The 22q11 deletion syndromes. Hum Mol Genet. 2000; 9:2421– 2426.

Abnormal development of the pharyngeal arches and pharyngeal pouches gives rise to the cardinal physical manifestations of the syndrome: conotruncal anomaly, hypocalcemia due to dysfunctional parathyroid glands, palatal abnormalities and paediatric immunodeficiency that may be secondary to hypo/aplasia of the thymus (Lindsay et al. 2001; Scambler 2000). [...] Major heart defects are present in about 40% of cases while minor anomalies, e.g., of the aortic arch, may be identified only on cardiac ultrasonography. Overt cleft palate is rare, whereas submucous cleft palate associated with velopharyngeal insufficiency is characteristic of 22q11.2DS. [...] In contrast, the facial features are considered a constant manifestation of the syndrome (Guyot et al. 2001), although the overall facial appearance is not always readily identifiable even to informed clinicians. [...] Developmental delays and learning difficulties are very commonly associated, although severe intellectual disability (termed mental retardation in the DSM diagnostic system) is rare. Recurrent seizures are common, especially those related to hypocalcemia, and epilepsy may be present in about 5% of patients. Psychiatric conditions may be present in children and over 60% of patients develop treatable psychiatric disorders by adulthood (Bassett et al. 2005). This risk is a major concern for families. In particular, due to the high frequency of schizophrenia in 22q11.2DS patients, the 22q11.2 region is considered to be one of the main schizophrenia susceptibility loci in humans (Bassett and Chow 2008; Insel 2010).

[page 3]

The commonly deleted region in 22q11.2DS encompasses approximately 45 genes and the consequences of decreased gene dosage of multiple genes are believed to be involved in phenotypic expression (Meechan et al. 2010).

[page 5]

Evidence from multiple studies indicates that about 1% of individuals with schizophrenia in the general population have 22q11.2 deletions (Bassett et al. 2010).

[page 8]

As clinical variability is not explained by differences in gene content within the deletion, allelic variation(s) in the non-deleted homologous region is considered a possible contributor to phenotypic variability. [...]

[...]

[...] Most of the genes from the 22q11.2 deletion region are expressed in fetal and adult brain, thus are candidates for both the psychiatric phenotype of patients with 22q11.2 deletions and susceptibility to psychiatric disorders in the general population (Meechan et al. 2010).


Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet Part A. 2005; 138:307–313. [PubMed: 16208694]

Bassett AS, Costain G, Fung WLA, Russell KJ, Pierce L, Kapadia R, Carter RF, Chow EW, Forsythe PJ. Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J Psychiatr Res. 2010; 44:1005–1009. [PubMed: 20643418]

Guyot L, Dubuc M, Pujol J, Dutour O, Philip N. Craniofacial anthropometric analysis in patients with 22q11 microdeletion. Am J Med Genet. 2001; 100:1–8. [PubMed: 11337741]

Insel TR. Rethinking schizophrenia. Nature. 2010; 468:187–193. [PubMed: 21068826]

Lindsay EA, Baldini A. Recovery from arterial growth delay reduces penetrance of cardiovascular defects in mice deleted for the DiGeorge syndrome region. Hum Mol Genet. 2001; 10:997–1002. [PubMed: 11309372]

Meechan DW, Maynard TM, Tucker ES, Lamantia AS. Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes. Int J Dev Neurosci. 2010 in press.

Scambler PJ. The 22q11 deletion syndromes. Hum Mol Genet. 2000; 9:2421–2426. [PubMed: 11005797]

Anmerkungen

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Introduction

Autism spectrum disorders (ASDs) represent a group of neurodevelopmental disorders that are characterized by impaired reciprocal social interactions, delayed or aberrant communication, and stereotyped, repetitive behaviours, often with restricted interests (Hu 2011). The prevalence for these disorders is now estimated at 1% (Gillbert 1999, Forbonne 2003, Kogan 2009). With a concordance rate as high as 90% in monozygotic twins and 2-10% in dizygotic twin pairs (Folstein 2001), ASD is among the most heritable of neuropsychiatric conditions. [...] Thus a considerable amount of effort has been devoted to identifying genetic mutations or variants that associate with these disorders.


5. Folstein SE, Rosen-Sheidley B. 2001. Genetics of autism: Complex aaetiology for a heterogeneous disorder. Nat Rev Genet 2(12): 943–955.

6. Fombonne E. 2003. Epidemiological surveys of autism and other pervasive developmental disorders: An update. J Autism Dev Disord 33(4): 365–382.

9. Gillberg C, Wing L. 1999. Autism: Not an extremely rare disorder. Acta Psychiatr Scand 99(6): 399–406.

11. Hu VW, Addington A, Hyman A. Novel autism subtype-dependent genetic variants are revealed by quantitative trait and subphenotype association analyses of published GWAS data. PLoS One. 2011 Apr 27;6(4):e19067.

Introduction

Autism spectrum disorders (ASDs) represent a group of neurodevelopmental disorders that are characterized by impaired reciprocal social interactions, delayed or aberrant communication, and stereotyped, repetitive behaviors, often with restricted interests [1,2]. With a concordance rate as high as 90% based on twin studies [3], ASDs are among the most heritable of neuropsychiatric conditions. [...] Thus, a considerable amount of effort has been devoted to identifying genetic mutations or variants that associate with these perplexing and often devastating, life-long disorders.


1. American Psychological Association (1994) Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychological Association.

2. Volkmar FR (1991) DSM-IV in progress. autism and the pervasive developmental disorders. Hosp Community Psychiatry 42(1): 33–5.

3. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, et al. (1995) Autism as a strongly genetic disorder: Evidence from a british twin study. Psychol Med 25(1): 63–77.

4. Feng Y, Zhang F, Lokey LK, Chastain JL, Lakkis L, et al. (1995) Translational suppression by trinucleotide repeat expansion at FMR1. Science 268(5211): 731–4.

5. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, et al. (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpGbinding protein 2. Nat Genet 23(2): 185–8.

6. Kim SJ, Cook EH, Jr. (2000) Novel de novo nonsense mutation of MECP2 in a patient with rett syndrome. Hum Mutat 15(4): 382–3.

7. Smalley SL, Burger F, Smith M (1994) Phenotypic variation of tuberous sclerosis in a single extended kindred. J Med Genet 31(10): 761–765.

8. Zhou CY, Wu KY, Leversha MA, Furlong RA, Ferguson-Smith MA, et al. (1995) Physical analysis of the tuberous sclerosis region in 9q34. Genomics 25(1): 304–308.

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[14.] Mmu/Fragment 014 01 - Diskussion
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1.5 Copy number variation and phenotypic variability.

Is now known that any individual carries ~1000 CNV ranging from 443 bp to 1.28 Mb (Conrad et al 2010). This can lead to either too many or too few dosage sensitive genes, which might result in phenotypic variability, complex behavioural traits and disease susceptibility. Interestingly, CNVs have not only been associated with disease, but also with genome evolution and adaptive traits. The AMY1 gene, which encodes a protein that catalyses the first step in digestion of dietary starch and glycogen, constitutes an interesting example. It has been found that the copy number of this gene is three times higher in humans compared to chimpanzees, suggesting that humans were favoured in the gene dosage due to a concomitant increase of starch consumption (Perry et al,2007). However, it still remains the problem to understand if CNV means disease and how these structural changes and gene dosage alterations contribute on phenotypic outcomes. Actually we know that CNVs affected specific genes or chromosomal region, can lead to susceptibility and predisposition to certain diseases such as HIV, lupus, nephritis, pancreatitis and psoriasis among many other phenotypes (Canales 2011). However, it has been shown that individuals carrying the same rearrangement, for instance within an affected family, show differences in the manifestation of the investigated phenotype.

[...] Further studies demonstrated that the variability can be due to the presence of an additional large deletion or duplication in the proband that resulted in a sensitized genetic background and consequently a more pronounced phenotype (Girirajan 2010).


14. Canales CP & Walz K. Copy number variation and susceptibility to complex traits. EMBO Mol Med. 2011 Jan;3(1):1-4.

19. Conrad DF, et al. Origins and functional impact of copy number variation in the human genome. Nature. 2010 Apr 1;464(7289):704-12.

23. Girirajan S. & Eichler E.E., Phenotypic variability and genetic susceptibility to genomic disorders. Human Molecular Genetics, 2010, Vol. 19, Review.

59. Perry GH, et al. Diet and the evolution of human amylase gene copy number variation. Nat Genet. 2007 Oct;39(10):1256-60.

This can lead to either too many or too few dosage sensitive genes, which might result in phenotypic variability, complex behavioural traits and disease susceptibility. Interestingly, CNVs have not only been associated with disease, but also with genome evolution and adaptive traits. The AMY1 gene, which encodes a protein that catalyzes the first step in digestion of dietary starch and glycogen, constitutes an interesting example. It has been found that the copy number of this gene is three times higher in humans compared to chimpanzees, suggesting that humans were favoured in the gene dosage due to a concomitant increase of starch consumption. [...] (Perry et al, 2007).

[page 3]

Moreover, it was found that any individual in average carries ∼1000 CNV ranging from 443 bp to 1.28 Mb, with a median size of 2.9 kb (Conrad et al, 2010). [...]

[...] Another important question is the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes. [...]

Importantly, today we can assert that many CNVs, which affect specific genes and chromosomal regions, can lead to susceptibility and predisposition to certain diseases such as HIV, lupus, nephritis, pancreatitis and psoriasis among many other phenotypes. However, often the simple gene dosage difference cannot explain a certain difference in phenotype. It has been shown, for example that individuals who carry the same dosage for a particular gene or region, for instance within an affected family, show differences in the manifestation of the investigated phenotype. [...] Further studies demonstrated that the differences in the phenotypic variability were due to the presence of an additional large deletion or duplication (second hit) in the probands that resulted in a sensitized genetic background and consequently a more pronounced phenotype. [...] (Girirajan et al, 2010a,b), [...]


1. Conrad D, et al. Nature. 2010;464:704–712.

3. Girirajan S, et al. Nat Genet. 2010a;42:203–209.

6. Perry GH, et al. Nat Genet. 2007;39:1256–1260.

Anmerkungen

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Perry et al. (2007) does not contain the parallel text.

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[15.] Mmu/Fragment 010 10 - Diskussion
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Therefore, the application of aCGH has created a paradigm shift in genetics that has moved the description and discovery of genetic conditions from the "phenotype-first" approach, in which patients exhibiting similar clinical features are identified prior to the discovery of an underlying aetiology, to a "genotype-first" approach, in which a collection of individuals with similar copy-number imbalances can be examined for common clinical features (Neill 2010).

56. Neill N.J., et al., Comparative analysis of copy number detection by whole-genome BAC and oligonucleotide array CGH. Mol Cytogenet, 2010. 3: p. 11.

Furthermore, the application of aCGH has created a paradigm shift in genetics that has moved the description and discovery of genetic conditions from the "phenotype-first" approach, in which patients exhibiting similar clinical features are identified prior to the discovery of an underlying etiology, to a "genotype-first" approach, in which a collection of individuals with similar copy-number imbalances can be examined for common clinical features. [38]

38. Neill, N.J., et al., Comparative analysis of copy number detection by whole-genome BAC and oligonucleotide array CGH. Mol Cytogenet, 2010. 3: p. 11.

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Nearly identical with identical reference. Nothing has been marked as a citation.

The text can also be found in the source given: see Mmu/Fragment_010_10b

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[16.] Mmu/Fragment 010 10b - Diskussion
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Therefore, the application of aCGH has created a paradigm shift in genetics that has moved the description and discovery of genetic conditions from the "phenotype-first" approach, in which patients exhibiting similar clinical features are identified prior to the discovery of an underlying aetiology, to a "genotype-first" approach, in which a collection of individuals with similar copy-number imbalances can be examined for common clinical features (Neill 2010).

56. Neill N.J., et al., Comparative analysis of copy number detection by whole-genome BAC and oligonucleotide array CGH. Mol Cytogenet, 2010. 3: p. 11.

Furthermore, the application of aCGH has created a paradigm shift in genetics that has moved the description and discovery of genetic conditions from the “phenotype-first”

approach, in which patients exhibiting similar clinical features are identified prior to the discovery of an underlying etiology, to a “genotype-first” approach, in which a collection of individuals with similar copy-number imbalances can be examined for common clinical features [15].


15. Shaffer LG, Theisen A, Bejjani BA, Ballif BC, Aylsworth AS, Lim C, McDonald M, Ellison JW, Kostiner D, Saitta S, Shaikh T: The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome. Genet Med 2007, 9:607-616.

Anmerkungen

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[17.] Mmu/Fragment 031 03 - Diskussion
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Bruno and colleagues identified two classes of co-locating microduplications in 17p13.3: class I duplications including YWHAE but not PAFAH1B1; and class II duplications always including PAFAH1B1, and sometimes including the genomic region encompassing the CRK and YWHAE genes [11]. Class I microduplications are associated with intellectual disability (ID), subtle dysmorphic facial features, subtle hand/foot malformations, and a tendency toward postnatal overgrowth [11]. Class II microduplications recently have been shown to be associated with mild to moderate ID and hypotonia. Some dysmorphic features, such as prominent forehead and pointed chin, are shared with class I duplications, while overgrowth, behavioural problems and hand/foot abnormalities are less often noted.

[11] Bruno D L, Anderlid B M, Lindstrand A, van Ravenswaaij-Arts C, Ganesamoorthy D, Lundin J, Martin C L, Douglas J, Nowak C, Adam M P, Kooy R F, Van der Aa N, et al. Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes. J Med Genet 47:299-311

We suggest that there are two classes of co-locating microduplications in 17p13.3. Class I duplications (six cases) involve YWHAE (encoding 14-3-3e), but notably not PAFAH1B1.12 Class II duplications (seven cases) always involve PAFAH1B1 and may also include the genomic region encompassing the CRK and YWHAE genes.12 14 Class I show autistic manifestations and other behavioural symptoms, speech and motor delay, subtle dysmorphic facial features, subtle hand/foot malformations, and a tendency to postnatal overgrowth (table 2). Class II microduplications have recently been shown to be associated with moderate to mild developmental and psychomotor delay and hypotonia. Some dysmorphic features, such as prominent forehead and pointed chin, are shared with the class I duplications, while overgrowth, behavioural problems and hand/foot abnormalities are less often noted (table 3).

12. Bi W, Sapir T, Shchelochkov OA, Zhang F, Withers MA, Hunter JV, Levy T, Shinder V, Peiffer DA, Gunderson KL, Nezarati MM, Shotts VA, Amato SS, Savage SK, Harris DJ, Day-Salvatore DL, Horner M, Lu XY, Sahoo T, Yanagawa Y, Beaudet AL, Cheung SW, Martinez S, Lupski JR, Reiner O. Increased LIS1 expression affects human and mouse brain development. Nat Genet 2009;41:168e77.

14. Roos L, Jonch AE, Kjaergaard S, Taudorf K, Simonsen H, Hamborg-Petersen B, Brondum-Nielsen K, Kirchhoff M. A new microduplication syndrome encompassing the region of the Miller-Dieker (17p13 deletion) syndrome. J Med Genet 2009;46:703e10.

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[18.] Mmu/Fragment 037 20 - Diskussion
Bearbeitet: 22. December 2014, 15:35 Hindemith
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The presence of microcephaly in both Patient 2 and her mother led us to consider disrupted genes at the breakpoints as possible candidate causes of microcephaly. The breakpoint at chromosome 17 did not disrupt genes, while the breakpoint at chromosome 9 interrupted the C9orf68 gene, which has a sequence homology to SPATA6, encoding for a spermatogenesis-associated protein 6 precursor. A dosage alteration of genes located near the breakpoints due to a positional effect cannot be excluded as a possible cause for the microcephaly present both in the patient and her mother. [Page 71]

The presence of microcephaly in both the patient and the mother induced us to

[Page 72]

consider disrupted genes at the breakpoints as possible candidates for microcephaly. The breakpoint on chromosome 17 seems not to disrupt genes, while the breakpoint on chromosome 9 seems to interrupt the gene C9orf68, which has a sequence homologous to SPATA6, encoding for a spermatogenesis-associated protein 6 precursor. Given the associated function, this gene doesn’t seem to contribute to the phenotype of our patient. A dosage alteration of genes located near the breakpoints due to a positional effect cannot be excluded as a possible cause for the microcephaly present both in the patient and her mother.

Anmerkungen

Nothing has been marked as a citation.

The original text is part of an article which is included in Katzaki's thesis. The patient described here is obviously the same (albeit now several years older). Mmu was not one of the coauthors of the original article. There is no hint given that this description is not Mmu's own. Neither is there a hint given that this patient's genetic material has been analyzed in a different context before.

The take-over from the original text is continued from Mmu/Fragment_037_01.

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[19.] Mmu/Fragment 037 01 - Diskussion
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[Deletions of the terminal portion of the short arm of chromosome 9 are associated with ID due to DOCK8 haploinsufficiency [34, 35] and a male to female sex] reversal, possibly due to DMRT1 and DMRT2 haploinsufficiency [23]. Although in female patients no urogenital anomalies are reported, we cannot completely rule out the hypothesis that the mild abnormal morphology of the uterus reported in our patient could be due to haploinsufficiency of the 9p region. Therefore, more accurate gynaecologic evaluation in the proband could be useful.

The rearrangements present in our patients originated from a balanced translocation present in a parent as demonstrated by FISH analysis. In family 2, the mother presented isolated microcephaly with normal intellectual functioning, and experienced two spontaneous miscarriages in the first month of gestation. In addition, the family history revealed that, two maternal cousins of the proband suffered from psychomotor delay. All these data indicated a segregation of the translocation in the maternal branch of the family.


[23] Barbaro M, Balsamo A, Anderlid B M, Myhre A G, Gennari M, Nicoletti A, Pittalis M C, Oscarson M, Wedell A. (2009) Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA. Eur J Hum Genet 17:1439-47

[34] Griggs B L, Ladd S, Saul R A, DuPont B R, Srivastava A K. (2008) Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities. Genomics 91:195-202

[35] Ruusala A, Aspenstrom P. (2004) Isolation and characterisation of DOCK8, a member of the DOCK180-related regulators of cell morphology. FEBS Lett 572:159-66

Deletions of the terminal portion of the short arm of chromosome 9 are associated with a male to female sex reversal, possibly due to DMRT1 and DMRT2 haploinsufficiency [Barbaro et al. 2009]. [...] Although in female patients no urogenital anomalies are reported, we cannot completely rule out the hypothesis that the mild abnormal morphology of the uterus reported in our patient could be due to haploinsufficiency of the 9p region. We therefore planned an accurate gynecologic evaluation in the proband.

The rearrangement present in our case is originated by a balanced translocation present in the mother as demonstrated by FISH analysis. The mother presents isolated microcephaly with normal psychomotor development and mental abilities and experienced two spontaneous abortions in the first month of gestation. In addition, from the family history, two maternal cousins of the proband are referred to suffer from psychomotor delay. All this data indicate a segregation of the translocation in the maternal branch of the family.

Anmerkungen

Nothing has been marked as a citation.

The original text is part of an article which is included in Katzaki's thesis. The patient described here is obviously the same (albeit now several years older). Mmu was not one of the coauthors of the original article. There is no hint given that this description is not Mmu's own. Neither is there a hint given that this patient's genetic material has been analyzed in a different context before.

The take-over from the original text is continued in Mmu/Fragment_037_20.

The reference for [Barbaro et al. 2009] is missing in Katzaki (2009).

Sichter
(Graf Isolan), SleepyHollow02

[20.] Mmu/Fragment 035 16 - Diskussion
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Erstellt: 20. December 2014, 12:41 (Graf Isolan)
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FISH analysis of the parents of both patients, performed using telomeric probes for chromosomes 10 and 17 in family 1 and probes for chromosomes 9 and 17 in family 2, revealed a balanced translocation in Patient 1’s father and Patient 2’s mother (data not shown). Given the presence of microcephaly in the otherwise healthy mother of Patient 2, we also performed array-CGH analysis on the mother’s DNA, to ascertain if the translocation was balanced. The analysis revealed no gains or losses at both breakpoints (data not shown). FISH analysis in parents performed using telomeric probes for chromosomes 9 and 17 revealed a balanced translocation in the mother (data not shown). Given the presence of microcephaly in the otherwise healthy mother, we also performed array-CGH analysis on the mother’s DNA, in order to ascertain if the translocation was balanced. The analysis revealed no gains or losses at both breakpoints. Given the presence of microcephaly in the otherwise healthy mother, we tested her DNA by array-CGH analysis to ascertain if the translocation is indeed balanced.
Anmerkungen

Nothing has been marked as a citation. Take-over is direct continuation from Mmu/Fragment_035_08.

The original text is part of an article which is included in Katzaki's thesis. The patient described here is obviously the same (albeit now several years older). Mmu was not one of the coauthors of the original article. There is no hint given that this description is not Mmu's own. Neither is there a hint given that this patient's genetic material has been analyzed in a different context before.

Sichter
(Graf Isolan), SleepyHollow02

[21.] Mmu/Fragment 035 08 - Diskussion
Bearbeitet: 22. December 2014, 15:35 Hindemith
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Results

[...] The array-CGH analysis also revealed a 50 Kb duplication in Xq28 [arr Xq28(148,690,284-148,728,581)x3 mat] in the proband and her mother, already reported in healthy individuals and thus probably not associated with a phenotype [31] (data not shown).


[31] Sanlaville D, Prieur M, de Blois M C, Genevieve D, Lapierre J M, Ozilou C, Picq M, Gosset P, Morichon-Delvallez N, Munnich A, Cormier-Daire V, Baujat G, et al. (2005) Functional disomy of the Xq28 chromosome region. Eur J Hum Genet 13:579-85

RESULTS

[...] The array-CGH analysis also revealed a 50 Kb duplication in Xq28 in the proband and her mother, already reported in healthy individuals and thus probably not associated with a phenotype [Sanlaville et al 2005].


• Sanlaville D, Prieur M, de Blois MC, Genevieve D, Lapierre JM, Ozilou C, Picq M, Gosset P, Morichon-Delvallez N, Munnich A, Cormier-Daire V, Baujat G, Romana S, Vekemans M, Turleau C. Functional disomy of the Xq28 chromosome region. Eur J Hum Genet 2005 May 13(5):579-85.

Anmerkungen

Nothing has been marked as a citation. Take-over is continued in Mmu/Fragment_035_16.

The original text is part of an article which is included in Katzaki's thesis. The patient described here is obviously the same (albeit now several years older). Mmu was not one of the coauthors of the original article. There is no hint given that this description is not Mmu's own. Neither is there a hint given that this patient's genetic material has been analyzed in a different context before.

Sichter
(Graf Isolan), SleepyHollow02

[22.] Mmu/Fragment 033 06 - Diskussion
Bearbeitet: 22. December 2014, 15:35 Hindemith
Erstellt: 19. December 2014, 20:35 (Graf Isolan)
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Patient 2 is a 15 years and 4 months old girl, the second child of healthy unrelated parents (Fig.1c and Table 1). The mother had two spontaneous miscarriages in the first month of gestation. At the time of her birth, Patient 2’s mother and father were 26 and 29 years old, respectively. The proband had a healthy older brother and two maternal cousins referred with psychomotor delay (not available for testing). The girl was born after a prolonged labour at term of an uneventful pregnancy. At birth, weight was 3300 gr (50th percentile) and length was 51 cm (50-75th percentile). Apgar score and OFC measurements were not available. A pale haemangioma of the forehead was observed. Patient 2 showed developmental delay: she began to sit alone at 1.5 year, crawled at 2 years, began to walk independently at 2.5 years, and said the first words at 5 years. She never acquired sphincter control and frequently suffered from respiratory infections during childhood. At 4 years the patient was surgically treated for strabismus. A radiological examination of skeletal development of the left-hand wrist showed mild bone-age delay (chronological age 5 years and 8 months, bone-age corresponding to 5 years and 1 month). A radiological survey of hands and feet performed at 11 years and 6 months showed aplasia of a phalanx of the fifth finger of both feet and a medial notch of the second phalanx of II finger of the left hand. Repeated EEGs were alternatively normal or showed a mild disorganization of the deep rhythm. Results of ophtalmological evaluation were normal except for mild myopia (-1.25/-1.50 diopters). A pelvic ultrasound showed mild irregularities of the morphology of the uterus. The following investigations were normal: abdominal and cardiac ultrasound, brain MRI and karyotype. Physical examination of Patient 2 at 11y1m (Fig.1d) demonstrated normal height (145 cm; 25-50th percentile) and weight (40 kg; 50-75th percentile), microcephaly (OFC of 48 cm; <<3rd percentile), triangular face, with pointed chin, synophrys, thickening in the medial part and V-shaped eyebrows, open mouth, high and narrow palate, and hypoplastic 5th toe, more evident on the right side. The patient showed ataxic gait, rocking of the trunk in upright position, unmotivated laughter and sialorrhea. [Page 70]

Clinical Report

The patient, an 11 years and 6 months old girl, is the second child of healthy unrelated parents. The mother had two spontaneous abortions in the first month of gestation (Fig.1 a). At birth, mother and father were 26 and 29 years old, respectively. The proband has a healthy older son and two maternal cousins referred with psychomotor delay probably due to perinatal distress.

The girl was born after a prolonged labour at the end of an uneventful pregnancy. At birth, weight was 3300 gr (50th percentile) and length was 51 cm (50-75th percentile). Apgar scores and head circumference (OFC) measurements are not available. A pale haemangioma of the forehead was noticed. At 2 months of life the mother realized that the baby was not normally interactive. She showed developmental delay: she began to sit alone at 1.5 year, she crawled at 2 years, she began to walk independently at 2.5 years, she said the first words at 5 years and she has never acquired sphinteric control. She frequently suffered from respiratory infections during childhood. At 4 years she was surgically treated for strabismus.

An X-ray of the wrist of the proband performed at 5 years and 8 months showed mild bone-age delay (bone-age corresponding to 5 years and 1 month). An X-ray of the feet performed at 7 years and 5 months showed bilateral absence of the middle or distal phalanx of the 5th toe. An X-ray of the left hand pointed out the presence of a medial incisura in the distal metaphysis of the second phalanx of the second finger, while no abnormalities were found in the right hand. A pelvic ultrasound showed mild irregularities of the morphology of the uterus. Repeted EEGs were alternatively normal or showed a mild disorganization of the deep rhythm. Oftalmological [sic] examination resulted normal except for mild myopia (-1,25/- 1,50 diopters). The following investigations were normal: abdominal and cardiac ultrasounds, brain MRI, karyotype,

[Page 71]

FISH analysis for Rubinstein-Taiby syndrome and for Angelman syndrome.

She was first admitted to our genetic unit at the age of 11 years and 1 month. Physical examination showed: normal height (145 cm; 25-50th percentile) and weight (40 kg; 50-75th percentile), microcephaly (OFC of 48 cm; <<3rd percentile), triangular face, with pointed chin, synophrys, thick eyebrows in the medial part, open mouth, high and narrow palate and hypoplastic 5th toe of the feet, more evident on the right side (Fig.1b). The patient showed ataxic gait and rocking of the trunk in upright position.

Anmerkungen

Nothing has been marked as a citation.

The original text is part of an article which is included in Katzaki's thesis. The patient described here is obviously the same (albeit now several years older). Mmu was not one of the coauthors of the original article. There is no hint given that this description is not Mmu's own. Neither is there a hint given that this patient's genetic material has been analyzed in a different context before.

Sichter
(Graf Isolan), SleepyHollow02

[23.] Mmu/Fragment 034 01 - Diskussion
Bearbeitet: 22. December 2014, 15:35 Hindemith
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[At the] time of our examination Patient 2 had just begun to formulate sentences, always spoke to catch attention, displayed hyperactivity, and brought all objects to to her mouth. Patient 2’s mother exhibited isolated microcephaly (OFC 52 cm, <3rd percentile) and normal height (169 cm; 75-90th percentile). At the time of our examination she had just begun to formulate sentences, she was always speaking to catch attention, she showed hyperactivity and she used to bring everything to the mouth. Her mother showed isolated microcephaly (OFC 52 cm, <3rd percentile) and normal height (169 cm; 75-90th percentile).
Anmerkungen

Continued from previous page. Nothing has been marked as a citation.

The original text is part of an article which is included in Katzaki's thesis. The patient described here is obviously the same (albeit now several years older). Mmu was not one of the coauthors of the original article. There is no hint given that this description is not Mmu's own. Neither is there a hint given that this patient's genetic material has been analyzed in a different context before.

Sichter
(Graf Isolan), SleepyHollow02

[24.] Mmu/Fragment 006 13 - Diskussion
Bearbeitet: 22. December 2014, 15:35 Hindemith
Erstellt: 17. December 2014, 13:40 (Graf Isolan)
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This method is very useful for determining the origin of unknown genetic material, such as SMCs and other unbalanced rearrangements. However, CGH does not detect balanced rearrangements, the resolution is on the order of 5–10 Mb and consequently many genomic disorders cannot be detected (Yunis 1976). The need to screen the whole genome at a resolution that surpassed the existing technologies led to the implementation of microarray based CGH. The principle is very similar to that employed for traditional CGH, where two differentially labelled specimens are cohybridized in the presence of Cot1 DNA (Fig.2).

88. Yunis J: High resolution of human chromosomes. Science 1976; 191: 1268-1270.

[Page 16]

This method allows the investigation of the whole genome and is very useful for determining the origin of unknown genetic material, such as SMCs and other unbalanced rearrangements.5 However, CGH does not detect balanced rearrangements, and the resolution is on the order of 5–10Mb, and consequently many genomic disorders cannot be detected.3

[Page 18]

The need to screen the whole genome at a resolution that surpassed the existing technologies led to the implementation of microarray based CGH. The principle is very similar to that employed for traditional CGH, where two differentially labeled specimens are cohybridized in the presence of Cot1 DNA; however, instead of metaphase spreads, the hybridization targets are DNA substrates immobilized on a glass slide.5-7


3 Edelmann L, Hirschhorn K: Clinical utility of array CGH for the detection of chromosomal imbalances associated with mental retardation and multiple congenital anomalies. Ann N Y Acad Sci 2009; 1151: 157-166.

4 Yunis J: High resolution of human chromosomes. Science 1976; 191: 1268-1270.

5 Trask BJ: Fluorescence in situ hybridization: applications in cytogenetics and gene mapping. Trends Genet 1991; 7: 149-154.

6 Pinkel D, Segraves R, Sudar D et al: High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 1998; 20: 207-211.

7 Cai WW, Mao JH, Chow CW, Damani S, Balmain A, Bradley A: Genome-wide detection of chromosomal imbalances in tumors using BAC microarrays. Nat Biotechnol 2002; 20: 393-396.

Anmerkungen

Nothing has been marked as a citation. The wrong reference in Mmu can be found in Katzaki's list of references right behind the correct one.

Sichter
(Graf Isolan), SleepyHollow02

[25.] Mmu/Fragment 015 02 - Diskussion
Bearbeitet: 22. December 2014, 15:35 Hindemith
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1.6 Reciprocal duplication of the Miller-Dieker region.

The short arm of chromosome 17 is particularly prone to submicroscopical rearrangements due to a high density of low copy repeats. Thus, the proximal 17p region harbours regions with microdeletion and reciprocal microduplication syndromes, each caused by non-allelic homologous recombination: CMT1A (Charcot–Marie–Tooth syndrome type 1A) (MIM#118220), due to a duplication at 17p11.2; HNPP (hereditary neuropathy with liability to pressure palsies) (MIM#162500), due to a reciprocal deletion, Smith–Magenis syndrome (MIM#182290), caused by a deletion at 17p11.2; and the relatively recently described Potocki–Lupski syndrome (MIM#610883), due to a reciprocal duplication at 17p11.2 (Stankiewicz 2003; Potocki 2000). Deletions in the more distal region 17p13.3, including the PAFAH1B1 gene (encoding LIS1), result in the brain malformation lissencephaly, with reduced gyration of the cerebral surface and increased cortical thickening. Depending on the size of the deletion, the phenotype varies from isolated lissencephaly (ILS) (MIM#607432) to Miller–Dieker syndrome (MDS) (MIM#247200); the latter consists of severe grade ILS and additional characteristic dysmorphic features and malformations (Dobyns 1993). Deletions in MDS vary in size, from 0.1 to 2.9 Mb. The critical region differentiating ILS from MDS is approximately 400 Kb, and is referred to as the ‘‘MDS telemetric [sic] critical region’’ (Cardoso et al, 2003).


15. Cardoso C, et al. Refinement of a 400-kb critical region allows genotypoical differantiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003;72:918–30.

20. Dobyns WB, Reiner O, Carrozzo R, Ledbetter DH. Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. JAMA 1993;270:2838–42.

61. Potocki L, et al. Molecular mechanism for duplication 17p11.2-the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000;24:84–7.

76. Stankiewicz P, et al. Genome architecture catalyzes nonrecurrent chromosomal rearrangements. Am J Hum Genet 2003;72:1101–16.

The short arm of chromosome 17 is particularly prone to submicroscopical rearrangements due to a high density of low copy repeats. Thus, the proximal 17p region harbours regions with microdeletion and reciprocal microduplication syndromes, each caused by non-allelic homologous recombination: CMT1A (Charcot–Marie–Tooth syndrome type 1A), due to a duplication at 17p11.2; HNPP (hereditary neuropathy with liability to pressure palsies), due to a reciprocal deletion, Smith–Magenis syndrome, caused by a deletion at 17p11.2; and the relatively recently described Potocki–Lupski syndrome, due to a reciprocal duplication at 17p11.2.1 2

Deletions in the more distal region 17p13.3, including the PAFAH1B1 gene (encoding LIS1), result in the brain malformation lissencephaly, with reduced gyration of the cerebral surface and increased cortical thickening. Depending on the size of the deletion, the phenotype varies from isolated lissencephaly (ILS) to Miller–Dieker syndrome (MDS); the latter consists of severe grade ILS and additional characteristic dysmorphic features and malformations.3 Deletions in MDS vary in size, from 0.1 to 2.9 Mb. The critical region differentiating ILS from MDS is approximately 400 Kb, and is referred to as the ‘‘MDS telemeric critical region’’.4


1. Stankiewicz P, Shaw CJ, Dapper JD, Wakui K, Shaffer LG, Withers M, Elizondo L, Park SS, Lupski JR. Genome architecture catalyzes nonrecurrent chromosomal rearrangements. Am J Hum Genet 2003;72:1101–16.

2. Potocki L, Chen KS, Park SS, Osterholm DE, Withers MA, Kimonis V, Summers AM, Meshino WS, Anyane-Yeboa K, Kashork CD, Shaffer LG, Lupski JR. Molecular mechanism for duplication 17p11.2-the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000;24:84–7.

3. Dobyns WB, Reiner O, Carrozzo R, Ledbetter DH. Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. JAMA;270:2838–42.

4. Cardoso C, Leventer RJ, Ward HL, Toyo-oko K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH, Mutchinick OM, Hirosune S, Wynshaw-Boris A, Dobyns WB, Ledbetter DH. Refinement of a 400-kb critical region allows genotypoical differantiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003;72:918–30.

Anmerkungen

Although nearly identical nothing has been marked as a citation.

Sichter
(Graf Isolan), SleepyHollow02

[26.] Mmu/Fragment 031 16 - Diskussion
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The known 9p deletion syndrome was first described by Alfi et al. in 1973 [15]. This is an heterogeneous condition with variable deletion size characterized by ID, congenital malformations including trigonocephaly, congenital heart defect, anorectal and genital anomalies and dysmorphisms [16-19]. The critical region for the 9p deletion syndrome has been located between bands p22.3 and p24.1 [19]. The deletions of the more terminal part of chromosome 9p are rarer and some of them coexist in the same patient together with larger rearrangements in other chromosomes [20, 14, 21, 22]. Patients with deletions involving the 9p24.3 band show male to female sex reversal, possibly due to DMRT1 and DMRT2 haploinsufficiency [23, 24].

[14] Kohler A, Hain J, Muller U. (1994) Familial half cryptic translocation t(9;17). J Med Genet 31:712-4

[15] Alfi O, Donnell G N, Crandall B F, Derencsenyi A, Menon R. (1973) Deletion of the short arm of chromosome no.9 (46,9p-): a new deletion syndrome. Ann Genet 16:17-22

[16] Christ L A, Crowe C A, Micale M A, Conroy J M, Schwartz S. (1999) Chromosome breakage hotspots and delineation of the critical region for the 9pdeletion syndrome. Am J Hum Genet 65:1387-95

[17] Hauge X, Raca G, Cooper S, May K, Spiro R, Adam M, Martin C L. (2008) Detailed characterization of, and clinical correlations in, 10 patients with distal deletions of chromosome 9p. Genet Med 10:599-611

[18] Huret J L, Leonard C, Forestier B, Rethore M O, Lejeune J. (1988) Eleven new cases of del(9p) and features from 80 cases. J Med Genet 25:741-9

[19] Swinkels M E, Simons A, Smeets D F, Vissers L E, Veltman J A, Pfundt R, de Vries B B, Faas B H, Schrander-Stumpel C T, McCann E, Sweeney E, May P, et al. (2008) Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype. Am J Med Genet A 146A:1430-8

[20] Brisset S, Kasakyan S, L'Hermine A C, Mairovitz V, Gautier E, Aubry M C, Benkhalifa M, Tachdjian G. (2006) De novo monosomy 9p24.3-pter and trisomy 17q24.3-qter characterised by microarray comparative genomic hybridisation in a fetus with an increased nuchal translucency. Prenat Diagn 26:206-13

[21] Repetto G M, Wagstaff J, Korf B R, Knoll J H. (1998) Complex familial rearrangement of chromosome 9p24.3 detected by FISH. Am J Med Genet 76:306-9

[22] Saha K, Lloyd I C, Russell-Eggitt I M, Taylor D S. (2007) Chromosomal abnormalities and glaucoma: a case of congenital glaucoma associated with 9p deletion syndrome. Ophthalmic Genet 28:69-72

[23] Barbaro M, Balsamo A, Anderlid B M, Myhre A G, Gennari M, Nicoletti A, Pittalis M C, Oscarson M, Wedell A. (2009) Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA. Eur J Hum Genet 17:1439-47

[24] Muroya K, Okuyama T, Goishi K, Ogiso Y, Fukuda S, Kameyama J, Sato H, Suzuki Y, Terasaki H, Gomyo H, Wakui K, Fukushima Y, Ogata T. (2000) Sex-determining gene(s) on distal 9p: clinical and molecular studies in six cases. J Clin Endocrinol Metab 85:3094-100

A well known 9p deletion syndrome was first described by Alfi et al. in 1973 [Alfi et al. 1973]. This is an heterogeneous condition with variable deletion size characterized by mental retardation, congenital malformations including trigonocephaly, congenital heart defect, anorectal and genital anomalies and dysmorphisms [Huret et al 1988, Christ et al 1999, Hauge et al 2008, Swinkels et al. 2008]. The critical region for the deletion 9p deletion syndrome has been located between bands p22.3 and p24.1 [Swinkels et al. 2008]. The deletions of the more terminal part of chromosome 9p are rarer and some of them coexist in the same patient together with larger rearrangements in other chromosomes [Saha et al. 2007, Brisset et al. 2006, Repetto et al. 1998]. Patients with deletions involving the 9p24.3 band show male to female sex reversal, possibly due to DMRT1 and DMRT2 haploinsufficiency [Muroya et al. 2000, Barbaro et al. 2009].

---

• Alfi O, Donnell GN, Crandall BF, Derencsenyi A, Menon R. Deletion of the short arm of chomosome no.9 (46,9p-): a new deletion syndrome. Ann Genet. 1973 Mar;16(1):17-22.

• Huret JL, Leonard C, Forestier B, Rethoré MO, Lejeune J. Eleven new cases of del(9p) and features from 80 cases. J Med Genet. 1988 Nov;25(11):741-9.

• Muroya K, Okuyama T, Goishi K, Ogiso Y, Fukuda S, Kameyama J, Sato H, Suzuki Y, Terasaki H, Gomyo H, Wakui K, Fukushima Y, Ogata T. Sex-determining gene(s) on distal 9p: clinical and molecular studies in six cases. J. Clin. Endocr. Metab. 85: 3094-3100, 2000.

• Swinkels ME, Simons A, Smeets DF, Vissers LE, Veltman JA, Pfundt R, de Vries BB, Faas BH, Schrander- Stumpel CT, McCann E, Sweeney E, May P, Draaisma JM, Knoers NV, van Kessel AG, van Ravenswaaij-Arts CM. Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype. Am J Med Genet A. 2008 Jun 1;146A(11):1430-8.

Anmerkungen

Nothing has been marked as a citation.

References for Christ et al 1999, Hauge et al 2008, Saha et al. 2007, Brisset et al. 2006, and Barbaro et al. 2009 are missing in Katzaki (2009).

Sichter
(Graf Isolan) Singulus

[27.] Mmu/Fragment 006 13b - Diskussion
Bearbeitet: 17. December 2014, 13:43 Graf Isolan
Erstellt: 4. November 2014, 21:17 (Graf Isolan)
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This method is very useful for determining the origin of unknown genetic material, such as SMCs and other unbalanced rearrangements. However, CGH does not detect balanced rearrangements, the resolution is on the order of 5–10 Mb and consequently many genomic disorders cannot be detected (Yunis 1976). The need to screen the whole genome at a resolution that surpassed the existing technologies led to the implementation of microarray based CGH. The principle is very similar to that employed for traditional CGH, where two differentially labelled specimens are co-hybridized in the presence of Cot1 DNA (Fig.2).

88. Yunis J: High resolution of human chromosomes. Science 1976; 191: 1268-1270.

[Page 10]

This method allows the investigation of the whole genome and is very useful for determining the origin of unknown genetic material, such as SMCs and other unbalanced rearrangements. However, CGH does not detect balanced rearrangements, the resolution is on the order of 5–10 Mb and consequently many genomic disorders cannot be detected. [4]

[Page 12]

The need to screen the whole genome at a resolution that surpassed the existing technologies led to the implementation of microarray based CGH. The principle is very similar to that employed for traditional CGH, where two differentially labelled specimens are co-hybridized in the presence of Cot1 DNA.


4. Edelmann, L. and K. Hirschhorn, Clinical utility of array CGH for the detection of chromosomal imbalances associated with mental retardation and multiple congenital anomalies. Ann N Y Acad Sci, 2009. 1151: p. 157-66.

Anmerkungen

Nothing has been marked as a citation.

Sichter
(Graf Isolan), SleepyHollow02

[28.] Mmu/Fragment 016 08 - Diskussion
Bearbeitet: 16. December 2014, 09:34 Singulus
Erstellt: 15. December 2014, 19:26 (Graf Isolan)
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Weiss et al. reported a recurrent microdeletion on chromosome 16p11.2 in five of 751 families with one or more cases with ASD, in three of 299 ASD patients, in five of 512 children referred for ID and/or autism (Weiss 2008). The reciprocal duplication was found in 11 patients and in five controls. In another study, the same deletion was detected in four of 712 autistic patients and none of 837 controls (Kumar 2008). The latter study identified the reciprocal duplication in one autism case and two controls. Similarly, Marshall et al. detected two de novo 16p11.2 deletions in 427 families with autism (Marshall 2008). The authors stated that deletions and duplications of 16p11.2 carry substantial susceptibility to autism, and that the deletions appear to account for approximately 1% of cases.

37. Kumar RA, et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 2008;17:628e38.

48.Marshall CR, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008;82:477– 488.

86.Weiss LA, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008;358:667e75.

Weiss et al. reported a recurrent microdeletion on chromosome 16p11.2 in five of 751 families with one or more cases with ASD, in three of 299 ASD patients, in five of 512 children referred for MR and/or autism, and in two of 18,834 Icelandic controls who had not been screened for psychiatric or language disorders [22]. The reciprocal duplication was found in 11 patients and in five controls. In another study, the same deletion was detected in four of 712 autistic patients and none of 837 controls [10]. This study identified the reciprocal duplication in one autism case and two controls. Similarly, Marshall et al. detected two de novo 16p11.2 deletions in 427 families with autism [13]. In this series, the reciprocal duplication was also found twice. The authors stated that deletions and duplications of 16p11.2 carry substantial susceptibility to autism, and that the deletions appear to account for approximately 1% of cases.

[10] R.A. Kumar, S. KaraMohamed, J. Sudi, D.F. Condrad, C. Brune, J.A. Badner, T.C. Gilliam, N.J. Nowak, E.H. Cook jr., W.B. Dobyns, S.L. Christian, Recurrent 16p11.2 microdeletion [sic] in autism, Hum. Mol. Genet. 17 (2008) 628–638.

[13] C.R. Marshall, A. Noor, J.B. Vincent, A.C. Lionel, L. Feuk, J. Skaug, M. Shago, R. Moessner, D. Pinto, Y. Ren, B. Thiruvahindrapduram, A. Fiebig, S. Schreiber, J. Friedman, C.E. Ketelaars, Y.J. Vos, C. Ficicioglu, S. Kirkpatrick, R. Nicolson, L. Sloman, A. Summers, C.A. Gibbons, A. Teebi, D. Chitayat, R. Weksberg, A. Thompson, C. Vardy, V. Crosbie, S. Luscombe, R. Baatjes, L. Zwaigenbaum, W. Roberts, B. Fernandez, P. Szatmari, S.W. Scherer, Structural variation of chromosomes in autism spectrum disorder, Am. J. Hum. Genet. 82 (2008) 477–488.

[22] L.A. Weiss, D. Yiping Shen, J.M. Korn, D.E. Arking, D.T. Miller, R. Fossdal, E. Seamundsen, H. Stefansson, M.A.R. Ferreira, T. Green, O.S. Platt, D.M. Ruderfer, C.H. Walsh, D. Altshuler, A. Chakravarti, R.E. Tanzi, K. Stefansson, S.L. Santangelo, J.F. Gusella, P. Sklar, B.L. Wu, M.J. Daly, Association between microdeletion and microduplication at 16p11.2 and autism, N. Engl. J. Med. 358 (2007) 1–9.

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However, a number of disease-associated rearrangements are not explained readily by either the NAHR or NHEJ recombinational mechanisms. Lee et al, proposed a new DNA replication-based mechanism termed FoSTeS to parsimoniously explain the generation of these complex rearrangements in the human genome. According to the FoSTeS model, during DNA replication, the active replication fork can stall and switch templates using complementary template microhomology to anneal and prime DNA replication (Lee 2007). The rearrangements generated by FoSTeS can be diverse in scale, from genomic duplications affecting megabases of the human genome to small deletions involving a single gene or only one exon. These different sized rearrangements implicate FoSTeS in CNVs of all sizes and in the evolution of both human genomes and genes (Zhang 2009).

40. Lee JA, Carvalho CM, Lupski JR. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007 Dec 28;131(7):1235-47.

89. Zhang F., Carvalho C.M.B., Lupski J.R. Complex human chromosomal and genomic rearrangements. Trends Genet, 25 (2009), pp. 298–307

[Page 849]

The findings were inconsistent with a simple recombination-based mechanism such as NAHR or NHEJ. We proposed a new DNA replication-based mechanism termed FoSTeS to parsimoniously explain the generation of these complex rearrangements in the human genome1.

According to the FoSTeS model1, during DNA replication, the active replication fork can stall and switch templates using complementary template microhomology to anneal and prime DNA replication.

[Page 852]

Our data show that the rearrangements generated by FoSTeS/MMBIR can be diverse in scale, from genomic duplications affecting megabases of the human genome to small deletions involving a single gene or only one exon (Table 1). These different sized rearrangements implicate FoSTeS/MMBIR in CNVs of all sizes and in the evolution of both human genomes and genes.


1. Lee, J.A., Carvalho, C.M. & Lupski, J.R. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007).

Anmerkungen

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[30.] Mmu/Fragment 011 15 - Diskussion
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1.3.4 Identifying the genomic lesions in known conditions

The high resolution afforded by array CGH has been used to define candidate regions for putative genes responsible for human genetic diseases. [...] Vissers and colleagues (Vissers 2004) hybridized cell lines from two individuals with CHARGE syndrome onto a genome-wide array with a 1Mb resolution. The authors narrowed a candidate region for CHARGE syndrome on 8q12 based on data from two individuals, one with a ~5 Mb deletion and another with a more complex rearrangement comprising two deletions that overlapped that of the first deletion subject. These results allowed the authors to focus on only nine genes in the region and detect heterozygous mutations in the gene CHD7, which was eventually shown to be the gene for CHARGE syndrome. The high resolution of that array was crucial in refining the critical region for this disease and in reducing the number of candidate genes to be investigated further.


82. Vissers LE, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004 Sep;36(9):955-7.

The high resolution afforded by array CGH has been used to define candidate regions for putative genes responsible for human genetic diseases. For example, Vissers

et al9 hybridized cell lines from two individuals with CHARGE syndrome onto a genome-wide array with a 1-Mb resolution. The authors used a 918-BAC tiling resolution array to narrow a candidate region for CHARGE syndrome on 8q12 based on data from two individuals, one with a ~5-Mb deletion and another with a more complex rearrangement comprising two deletions that overlapped that of the first deletion subject. These results allowed the authors to focus on only nine genes in the region and detect heterozygous mutations in the gene CHD7, which was eventually shown to be the gene for CHARGE syndrome.9 The high resolution of that array was crucial in refining the critical region for this disease and in reducing the number of candidate genes to be investigated further.


9. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG: Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004, 36:955–957

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[31.] Mmu/Fragment 009 13 - Diskussion
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The resolution of array CGH is defined by two main factors: 1) the size of the nucleic acid targets and 2) the density of coverage over the genome; the smaller the size of the nucleic acid targets and the more contiguous the targets on the native chromosome, the higher the resolution of the array. The resolution of array CGH is defined by two main factors: 1) the size of the nucleic acid targets and 2) the density of coverage over the genome; the smaller the size of the nucleic acid targets and the more contiguous the targets on the native chromosome, the higher the resolution of the array.
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The clinical phenotypes associated with the reciprocal microduplications of the same genomic regions are, however, less well characterized probably because, in general, individuals with duplications tend to have a milder phenotype than those with the complementary deletions and this milder phenotype may not lead to clinical investigation (Van der Aa 2009; Hassed 2004; Potocki 2000). The introduction of aCGH in clinical practice has showed that the frequency of these duplications is much higher than heretofore appreciated. As aCGH becomes the primary method of testing individuals with even mild intellectual deficit/developmental delay (ID/DD), the frequency of microduplications at the common microdeletion syndrome loci will likely increase (Bejjani and Shaffer 2008).

7. Bejjani, B.A. & L.G. Shaffer, Clinical utility of contemporary molecular cytogenetics. Annu Rev Genomics Hum Genet, 2008. 9: p. 71-86.

27. Hassed S.J., et al., A new genomic duplication syndrome complementary to the velocardiofacial (22q11 deletion) syndrome. Clin Genet, 2004. 65(5): p. 400-4.

61. Potocki L, et al. Molecular mechanism for duplication 17p11.2-the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000;24:84–7.

81. Van der Aa N., et al., Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet, 2009. 52(2-3): p. 94-100.

However, duplications have not been observed until fairly recently, likely because, in

general, individuals with duplications tend to have a milder phenotype than those with the complementary deletions [43] [44] [45] [46] [47] and this milder phenotype may not lead to clinical investigation. [48] [49] The introduction of aCGH in clinical practice has virtually eliminated all the technical impediments of traditional cytogenetics and FISH and allowed the detection of such conditions with relative-but not complete-independence from the clinician's diagnostic judgment. Therefore, recent reviews of cohorts of patients ascertained with aCGH showed that the frequency of these duplications is much higher than heretofore appreciated. As aCGH becomes the primary method of testing individuals with even mild DD/ID, the frequency of microduplications at the common microdeletion syndrome loci will likely increase. [37] [50]


37. Bejjani, B.A. and L.G. Shaffer, Clinical utility of contemporary molecular cytogenetics. Annu Rev Genomics Hum Genet, 2008. 9: p. 71-86.

43. Berg, J.S., et al., Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genet Med, 2007. 9(7): p. 427-41.

44. Potocki, L., et al., Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet, 2007. 80(4): p. 633-49.

45. Yobb, T.M., et al., Microduplication and triplication of 22q11.2: a highly variable syndrome. Am J Hum Genet, 2005. 76(5): p. 865-76.

46. Brunetti-Pierri, N., et al., Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet, 2008. 40(12): p. 1466-71.

47. Van der Aa, N., et al., Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet, 2009. 52(2-3): p. 94-100.

48. Hassed, S.J., et al., A new genomic duplication syndrome complementary to the velocardiofacial (22q11 deletion) syndrome. Clin Genet, 2004. 65(5): p. 400-4.

49. Potocki, L., et al., Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet, 2000. 24(1): p. 84-7.

50. de Vries, B.B., et al., Diagnostic genome profiling in mental retardation. Am J Hum Genet, 2005. 77(4): p. 606-16.

Anmerkungen

Shortened but otherwise nearly identical. The list of references has been shortened, too, but here also copying has taken place (detectable by the placement of the year - which this time is not right behind the authors' names - and the usage of "p." in front of the pagenumbers, which is not done by Mmu in general). Nothing has been marked as a citation.

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[33.] Mmu/Fragment 010 22 - Diskussion
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A more complete understanding of the full clinical spectrum of these disorders will be achieved as the use of aCGH in the clinic becomes more prevalent and as correlations of these clinical findings with the genomic lesions are made. A more complete understanding of the full clinical spectrum of these disorders will be achieved as the use of aCGH in the clinic becomes more prevalent and as correlations of these clinical findings with the genomic lesions are made.
Anmerkungen

Identical. Nothing has been marked as a citation.

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[34.] Mmu/Fragment 087 03 - Diskussion
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The first theory, referred as the “common gene/common disease” hypothesis, is that common diseases result from the additive or multiplicative effects of genetic and environmental factors. Common genetic variants confer only a small increased risk to a given individual, but because of the high frequency with which these variants are found, each has a large attributable risk among the population (Weiss 2009). An alternative to the “common gene/common disease” hypothesis is that ASDs are caused not only by common variants of small effect but also by rare highly penetrant variants such as chromosomal deletions and duplications (Kusenda 2008). A substantial proportion of idiopathic autism may be attributable to CNVs. Two recent studies detected de novo CNVs in 7–10% of autistic cases from simplex families, 2–3% of cases from multiplex families, and in 1% of controls (Marshall 2008). These results not only implicate CNVs in the aetiology of autism but also indicate that different genetic mechanisms may underlie sporadic, versus familial, autism. Microdeletions and microduplications of chromosome 16p11.2 have been found at varying frequencies among individuals diagnosed with ASDs. Microdeletions are a more common cause of ASDs than the reciprocal microduplication (0.50% vs. 28%, respectively) (Walsh 2011).

39. Kusenda M & Sebat J. The role of rare structural variants in the genetics of autism spectrum disorders. Cytogenet Genome Res 2008;123:36–43.

48.Marshall CR, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008;82:477– 488.

83.Walsh KM & Bracken MB. Copy number variation in the dosage-sensitive 16p11.2 interval accounts for only a small proportion of autism incidence: a systematic review and meta-analysis. Genet Med. 2011 May;13(5):377-84.

85.Weiss LA, et al. A genome-wide linkage and association scan reveals novel loci for autism. Nature 2009;461:802– 808.

Microdeletions and microduplications of chromosome 16p11.2 have been found at varying frequencies among individuals diagnosed with an ASD.

[page 380]

The prevailing hypothesis for the genetic etiology of autism has largely been the same as that for other common diseases and is widely referred to as the “common gene/common disease” hypothesis. The theory is that common diseases result from the additive or multiplicative effects of genetic and environmental factors. Under this paradigm, common genetic variants confer only a small increased risk to a given individual, but because of the high frequency with which these variants are found, each has a large attributable risk among the population. This hypothesis is readily tested using genome-wide association studies, and such studies have had some successes in unraveling autism biology.31–33

An alternative to the “common gene/common disease” hypothesis is that ASDs are caused not only by common variants of small effect but also by rare highly penetrant variants such as chromosomal deletions and duplications.34 [...]

A substantial proportion of idiopathic autism may be attributable to CNVs.34 Two recent studies detected de novo CNVs in 7–10% of autistic cases from simplex families, 2–3% of cases from multiplex families, and in 1% of controls.16,18 These results not only implicate CNVs in the etiology of autism but also indicate that different genetic mechanisms may underlie sporadic, versus familial, autism.

[page 381]

[...] microdeletions are a more common cause of ASDs than the reciprocal microduplication (0.50% vs. 28%, respectively).


16. Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008;82:477– 488.

18. Sebat J, Lakshmi B, Malhotra D, et al. Strong association of de novo copy number mutations with autism. Science 2007;316:445– 449.

31. Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins, the Autism Consortium, Daly MJ, Chakravarti A. A genome-wide linkage and association scan reveals novel loci for autism. Nature 2009;461:802– 808.

32. Ma D, Salyakina D, Jaworski JM, et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann Hum Genet 2009;73(Pt 3):263–273.

33. Autism Genome Project Consortium, Szatmari P, Paterson AD, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007;39:319 –328.

34. Kusenda M, Sebat J. The role of rare structural variants in the genetics of autism spectrum disorders. Cytogenet Genome Res 2008;123:36–43.

Anmerkungen

The source is mentioned at the end, but the reader cannot know that also the passages referenced with other literature are taken from the source.

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[35.] Mmu/Fragment 007 01 - Diskussion
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Fig.2 Schematic representation of an array-CGH experiment. Test and reference DNA are differentially labelled, co-precipitated and hybridised to an array. After wash procedures, the slides are analysed through a scanner and fluorescence intensities of each probe are determined. After imaging processing and data normalization, the log2 ratios of the probes are plotted as a function of chromosomal position. Probes with a value of zero represent equal fluorescence intensity ratio between sample and reference. In this representation, copy number loss shift the ratio to the left and copy number gains shift the ratio to the right. Fig. 2 Schematic representation of an array-CGH experiment. a) Test and reference DNA are differentially labelled, co-precipitated and hybridised to an array. b) and c) After wash procedures, the slides are analysed through a scanner and fluorescence intensities of each probe are determined. d) After imaging processing and data normalization, the log2 ratios of the probes are plotted as a function of chromosomal position. Probes with a value of zero represent equal fluorescence intensity ratio between sample and reference. [...] In this representation, copy number loss shift the ratio to the left and copy number gains shift the ratio to the right.
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[36.] Mmu/Fragment 009 01 - Diskussion
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Several different platforms are available for oligonucleotide arrays that range from 25- to 85mers in length, some of which were adapted from genome-wide SNP-based oligonucleotide markers and others that were created from a library of virtual probes that span the genome, and consequently can be constructed to have extremely high resolution (Shaikh 2007). Both BAC and oligonucleotide arrays have been used successfully to detect copy number changes in patients with intellectual deficit (ID), multiple congenital anomalies (MCA) and autism. A number of different array design approaches have been taken for diagnostic purposes. A targeted array is one that contains specific regions of the genome, such as the sub-telomeres and those responsible for known microdeletion/microduplication syndromes, but does not have probes that span the whole genome (Bejjani 2005, Bejjani 2006, Shaffer 2006). A whole genome or tiling path array offers full genome coverage with different resolution.

8. Bejjani, B.A. & L.G. Shaffer. 2006. Application of array-based comparative genomic hybridization to clinical diagnostics. J. Mol. Diagn. 8: 528–533.

9. Bejjani, B.A. et al. 2005. Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: Is less more? Am. J. Med. Genet. A 134: 259–267.

70. Shaffer L.G. et al. 2006. Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J. Pediatr.149: 98–102.

72. Shaikh, T.H. 2007. Oligonucleotide arrays for highresolution analysis of copy number alteration in mental retardation/multiple congenital anomalies. Genet. Med. 9: 617–625.

[Page 13]

Several different platforms are available for oligonucleotide arrays, some of which were adapted from genome wide SNP-based oligonucleotide markers and others that were created from a library of virtual probes that span the genome, and consequently can be constructed to have extremely high resolution. [10] Both BAC and

[Page 14]

oligonucleotide arrays have been used successfully to detect copy number changes in patients with ID/MCA and autism. A number of different array design approaches have been taken for diagnostic purposes. A targeted array is one that contains specific regions of the genome, such as the subtelomeres and those responsible for known microdeletion/microduplication syndromes, but does not have probes that span the whole genome. [11] [12] [13] [...] A whole genome or tiling path array offers full genome coverage with a resolution that is dependent on the spacing of the probes.


10. Shaikh, T.H., Oligonucleotide arrays for high-resolution analysis of copy number alteration in mental retardation/multiple congenital anomalies. Genet Med, 2007. 9(9): p. 617-25.

11. Bejjani, B.A., et al., Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: is less more? Am J Med Genet A, 2005. 134(3): p. 259-67.

12. Bejjani, B.A. and L.G. Shaffer, Application of array-based comparative genomic hybridization to clinical diagnostics. J Mol Diagn, 2006. 8(5): p. 528-33.

13. Shaffer, L.G., Risk estimates for uniparental disomy following prenatal detection of a nonhomologous Robertsonian translocation. Prenat Diagn, 2006. 26(4): p. 303-7.

Anmerkungen

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1.2 Array – CGH Methodologies

[...]

Two major types of array targets are currently being utilized. Initially, bacterial artificial chromosomes (BACs) were the array target of choice (Pinkel 1998). However, now oligonucleotide arrays have been adopted due to the increased genome coverage they afford. The design of both array types was made possible by the availability of the complete map and sequence of the human genome. The BAC arrays may contain DNA isolated from large insert clones that range in size from 150–200 kb, spotted directly onto the array or may employ the spotting of PCR products amplified from the BAC clones (Ylstra 2006). These arrays are generally very sensitive and results can be directly validated with FISH using the BAC DNA as a probe. However, production of BAC DNA is labor-intensive, and the resolution is limited to 50–100 kb, even on a whole genome tiling path array (Ishkanian 2004). Oligonucleotide arrays offer a flexible format with the potential for very high [resolution and customization.]


30. Ishkanian A.S. et al. 2004. A tiling resolution DNA microarray with complete coverage of the human genome. Nat. Genet. 36: 299–303.

60. Pinkel D. et al. 1998. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat. Genet. 20: 207–211.

87. Ylstra B. et al. 2006. BAC to the future! Or oligonucleotides: A perspective for micro array comparative genomic hybridization (array CGH). Nucleic Acids Res. 34: 445–450.

1.2 Array – CGH Methodologies

Two major types of array targets are currently being utilized. Initially, bacterial artificial chromosomes (BACs) were the array target of choice. [6] However, more recently, oligonucleotide arrays have been adopted due to the increased genome coverage they afford. The design of both array types was made possible by the availability of the complete map and sequence of the human genome. The BAC arrays may contain DNA isolated from large insert clones that range in size from 150–200 Kb, spotted directly onto the array or may employ the spotting of PCR products amplified from the BAC clones. [8] These arrays are generally very sensitive and results can be directly validated with FISH using the BAC DNA as a probe. However, production of BAC DNA is labor-intensive and the resolution is limited to 50–100 Kb, even on a whole genome tiling path array. [9] Oligonucleotide arrays offer a flexible format with the potential for very high resolution and customization.


6. Pinkel, D., et al., High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet, 1998. 20(2): p. 207-11.

8. Ylstra, B., et al., BAC to the future! or oligonucleotides: a perspective for micro array comparative genomic hybridization (array CGH). Nucleic Acids Res, 2006. 34(2): p. 445-50.

9. Ishkanian, A.S., et al., A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet, 2004. 36(3): p. 299-303.

Anmerkungen

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3) MATERIALS & METHODS

3.1 Patients collection

Patients with ID and MCA enrolled in this study have been selected among those referred the Medical Genetics Unit of the University Hospital of Siena. All patients were evaluated by clinical geneticists.

3.2 Array-based CGH

3.2.1 Samples preparation

Genomic DNA of normal controls was obtained from Promega. Genomic DNAs were extracted from peripheral blood samples using a QIAamp DNA Blood Maxi kit according to the manufacturer protocol (Qiagen, www.qiagen.com). The OD260/280 method on a photometer was employed to determine the appropriate DNA concentration (Sambrook 1989). Patient and control DNA samples were sonicated to produce a homogeneous smear DNA extending from approximately 600 bp to 2 Kb. DNA samples were then purified using the DNA Clean and Concentrator kit (Zymo Research, Orange, CA). Ten micrograms of genomic DNA both from the patient and from the control were sonicated. Test and reference DNA samples were subsequently purify using dedicated columns (DNA Clean and Concentrator, Zymo research, CA92867-4619, USA) and the appropriate DNA concentrations were determine by a DyNA Quant™ 200 Fluorometer (GE Healthcare).

3.2.2 Human oligonucleotides array

Array based CGH analysis was performed using commercially available oligonucleotide microarrays containing about 43,000 60-mer probes with an estimated average resolution of about 100-130 Kb (Human Genome CGH Microarray 44B Kit, Agilent Technologies) and microarrays containing 99,000 60- mer probes with an estimate average resolution of 50-65 Kb (Human Genome CGH [Microarray 105A Kit, Agilent Technologies).]


67. Sambrook, J. & M.J. Gething, Protein structure. Chaperones, paperones. Nature, 1989. 342(6247): p. 224-5.

3. MATERIALS & METHODS


3.1 Patients collection Patients with ID and MCA enrolled in this study have been selected among those attending the Medical Genetics Unit of the University Hospital of Siena. All they were evaluate in genetic counseling and a clinically recognizable condition was excluded a diagnosis of a recognizable syndrome, and all patients.

3.2 Array-based CGH

3.2.1 Samples preparation

Genomic DNA of normal controls was obtained from Promega. Genomic DNA was extracted from peripheral blood using a QIAamp DNA Blood Maxi kit according to the manufacturer protocol (Qiagen, www.qiagen.com). The OD260/280 method on a photometer was employed to determine the appropriate DNA concentration. [94] Patient and control DNA samples were sonicated to produce a homogeneous smear DNA extending from approximately 600 bp to 2 Kb. DNA samples were then purified using the DNA Clean and Concentrator kit (Zymo Research, Orange, CA). Ten micrograms of genomic DNA both from the patient and from the control were sonicated. Test and reference DNA samples were subsequently purify using dedicated columns (DNA Clean and Concentrator, Zymo research, CA92867-4619, USA) and the appropriate DNA concentrations were determine by a DyNA Quant™ 200 Fluorometer (GE Healthcare).

3.2.2 Human oligonucleotides array

Array based CGH analysis was performed using commercially available oligonucleotide microarrays containing about 43,000 60-mer probes with an

[page 29:]


estimated average resolution of about 100-130 Kb (Human Genome CGH Microarray 44B Kit, Agilent Technologies) and microarrays containing 99,000 60-mer probes with an estimate average resolution of 50-65 Kb (Human Genome CGH Microarray 105A Kit, Agilent Technologies).


94. Sambrook, J. and M.J. Gething, Protein structure. Chaperones, paperones. Nature, 1989. 342(6247): p. 224-5.

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Physical positions of the probes correspond to the UCSC genome browser - GRCh build 37, Feb 2009 (http://genome.ucsc.edu). DNA labelling was executed essentially according to the Agilent protocol (Oligonucleotide Array-Based CGH for Genomic DNA Analysis 2.0v) using the Bioprime DNA labelling system (Invitrogen). Genomic DNA (2 μg) was mixed with 20 μl of 2.5X Random primer solution (Invitrogen) and MilliQ water to a total volume of 41 μl. The mix was denaturated at 95° C for 7 minutes and then incubated in ice/water for 5 minutes. Each sample was added with 5 μl of 10X dUTP nucleotide mix (1.2 mM dATP, dGTP, dCTP, 0.6 mM dTTP in 10 mM Tris pH 8 and 1 mM EDTA), 2.5 μl of Cy5-dUTP (test sample) or 2.5 μl of Cy3-dUTP (reference sample) and with 1.5 μl of Exo-Klenow (40 U/μl, Invitrogen). Labeled samples were subsequently purified using CyScribe GFX Purification kit (Amersham Biosciences) according to the manufacturer protocol. Test and reference DNA were pooled and mixed with 50 μg of Human Cot I DNA (Invitrogen), 50 μl of Blocking buffer (Agilent Technologies) and 250 μl of Hybridization buffer (Agilent Technologies). Before hybridization to the array the mix was denatured at 95°C for 7 minutes and then pre-associated at 37°C for 30 minutes. Probes were applied to the slide using an Agilent microarray hybridization station. Hybridization was carried out for 24/40 hrs at 65°C in a rotating oven (20 rpm). The array was disassembled and washed according to the manufacturer protocol with wash buffers supplied with the Agilent kit. The slides were dried and scanned using an Agilent G2565BA DNA microarray scanner. Image analysis was performed using the CGH Analytics software v.3.4.40 with default settings. The software automatically determines the fluorescence intensities of the spots for both fluorochromes performing background subtraction and data normalization, and compiles the data into a spreadsheet that links the fluorescent signal of every oligo on the array to the oligo name, its position on the array and its position in the genome. The linear order of the oligos is reconstituted in the ratio plots consistent with an ideogram. The ratio plot is arbitrarily assigned such that gains and losses in DNA copy number at a particular locus are observed as a deviation of the ratio plot from a modal value of 1.0. Physical positions of the probes correspond to the UCSC genome browser - NCBI build 36, March 2006. (http://genome.ucsc.edu). DNA labelling was executed essentially according to the Agilent protocol (Oligonucleotide Array-Based CGH for Genomic DNA Analysis 2.0v) using the Bioprime DNA labelling system (Invitrogen). Genomic DNA (2 μg) was mixed with 20 μl of 2.5X Random primer solution (Invitrogen) and MilliQ water to a total volume of 41 μl. The mix was denaturated at 95° C for 7 minutes and then incubated in ice/water for 5 minutes. Each sample was added with 5 μl of 10X dUTP nucleotide mix (1.2 mM dATP, dGTP, dCTP, 0.6 mM dTTP in 10 mM Tris pH 8 and 1 mM EDTA), 2.5 μl of Cy5-dUTP (test sample) or 2.5 μl of Cy3-dUTP (reference sample) and with 1.5 μl of Exo-Klenow (40 U/μl, Invitrogen). Labeled samples were subsequently purified using CyScribe GFX Purification kit (Amersham Biosciences) according to the manufacturer protocol. Test and reference DNA were pooled and mixed with 50 μg of Human Cot I DNA (Invitrogen), 50 μl of Blocking buffer (Agilent Technologies) and 250 μl of Hybridization buffer (Agilent Technologies). Before hybridization to the array the mix was denatured at 95°C for 7 minutes and then pre-associated at 37°C for 30 minutes. Probes were applied to the slide using an Agilent microarray hybridization station. Hybridization was carried out for 24/40 hrs at 65°C in a rotating oven (20 rpm). The array was disassembled and washed according to the manufacturer protocol with wash buffers supplied with the Agilent kit. The slides were dried and scanned using an Agilent G2565BA DNA microarray scanner. Image analysis was performed using the CGH Analytics software v. 3.4.40 with default settings. The software automatically determines the fluorescence intensities of the spots for both fluorochromes performing

[page 30:]

background subtraction and data normalization, and compiles the data into a spreadsheet that links the fluorescent signal of every oligo on the array to the oligo name, its position on the array and its position in the genome. The linear order of the oligos is reconstituted in the ratio plots consistent with an ideogram. The ratio plot is arbitrarily assigned such that gains and losses in DNA copy number at a particular locus are observed as a deviation of the ratio plot from a modal value of 1.0.

Anmerkungen
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The PPYR1 gene is a key regulator of energy homeostasis and directly involved in the regulation of food intake. PPYR1, also named as neuropeptide Y receptor or pancreatic polypeptide 1, is a member of the seven transmembrane domain-G-protein coupled receptor family. Genetic variation studies have reinforced the potential influence of PPYR1 on body weight in humans. Pancreatic polypeptide is the preferential PPYR1 agonist. Peripheral administration of pancreatic polypeptide inhibits gastric emptying and decreases food intake in humans (Sha 2009). This effect is mediated by direct action on local PPYR1 within the arcuate nucleus. Sha et al, demonstrated that subjects with 10q11.22 loss had 12.4% higher BMI value, and subjects with 10q11.22 gain had 5.4% lower BMI value when compared to normal diploid subjects. PPYR1 null animals showed, for instance, an opposite result. Knockout mice displayed lower body weight and reduced white adipose tissue accompanied with increased plasma levels of pancreatic polypeptide (Sainsbury et al. 2002).

19. Sainsbury A, Schwarzer C, Couzens M, Fetissov S, Furtinger S, Jenkins A, Cox HM, Sperk G, Hökfelt T, Herzog H. Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8938-43. Epub 2002 Jun 18.

21. Sha BY, Yang TL, Zhao LJ, Chen XD, Guo Y, Chen Y, Pan F, Zhang ZX, Dong SS, Xu XH, Deng HW. Genome-wide association study suggested copy number variation may be associated with body mass index in the Chinese population. J Hum Genet. 2009 Apr;54(4):199-202. Epub 2009 Feb 20.

Association analyses showed that the CNV 10q11.22 loss was significantly associated with higher BMI. Compared with the 567 subjects with two gene copy numbers (normal diploid), subjects with CNV 10q11.22 loss had 12.4% higher BMI value, and subjects with CNV 10q11.22 gain had 5.4% lower BMI value (Figure 2). [...]

[...]

[...] The PPYR1 gene was a key regulator of energy homeostasis and directly involved in the regulation of food intake.25 PPYR1, also named as neuropeptide Y receptor or pancreatic polypeptide 1, was a member of the seven transmembrane domain-G-protein coupled receptor family. Genetic variation studies have reinforced the potential influence of PPYR1 on body weight in humans.26 Pancreatic polypeptide is the preferential PPYR1 agonist.27 Peripheral administration of pancreatic polypeptide inhibits gastric emptying and decreases food intake in humans.28,29

[page 5]

Sainsbury A et al.25 reported that PPYR1 knockout mice displayed lower body weight and reduced white adipose tissue accompanied with increased plasma levels of pancreatic polypeptide.


25. Sainsbury A, Schwarzer C, Couzens M, Jenkins A, Oakes S, Ormandy C, et al. Y4 receptor knockout rescues fertility in ob/ob mice. Genes Dev 2002;16:1077–1088. [PubMed: 12000791]

26. Kamiji M, Inui A. Neuropeptide y receptor selective ligands in the treatment of obesity. Endocr. Rev 2007;28:664–684. [PubMed: 17785427]

27. Berglund M, Hipskind P, Gehlert D. Recent developments in our understanding of the physiological role of PP-fold peptide receptor subtypes. Exp. Biol. Med. (Maywood.) 2003;228:217–244. [PubMed: 12626767]

28. Batterham R, Le Roux C, Cohen M, Park A, Ellis S, Patterson M, et al. Pancreatic polypeptide reduces appetite and food intake in humans. J. Clin. Endocrinol. Metab 2003;88:3989–3992. [PubMed: 12915697]

29. Schmidt P, Naslund E, Gryback P, Jacobsson H, Holst J, Hilsted L, et al. Arole for pancreatic polypeptide in the regulation of gastric emptying and short-term metabolic control. J. Clin. Endocrinol. Metab 2005;90:5241–5246. [PubMed: 15998783]

Anmerkungen

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[41.] Mmu/Fragment 006 01 - Diskussion
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SKY and m-FISH rely mainly on the principal of differentially labelling each chromosome using a unique combination of fluorochromes and are especially beneficial for identifying the origin and content of supernumerary marker chromosomes (SMCs) and complex chromosome rearrangements (CCRs) that involve more than two chromosomes (Fig.1c). SKY and m-FISH rely mainly on the principal of differentially labelling each chromosome using a unique combination of fluorochromes and are especially beneficial for identifying the origin and content of supernumerary marker chromosomes (SMCs) and complex chromosome rearrangements (CCRs) that involve more than two chromosomes.
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Therefore this method is still predominantly used when the clinical phenotype is suggestive of a particular disorder. Several other FISH-based methods, including spectral karyotyping (SKY), multicolour FISH (m-FISH), and comparative genomic hybridization (CGH) have proven extremely useful in the identification of unknown chromosomal material. There are currently a number of commercially available FISH probes for the most common disorders and this method is still predominantly used when the clinical phenotype is suggestive of a particular disorder. Several other FISH-based methods, including spectral karyotyping (SKY), multicolour FISH (m-FISH), and comparative genomic hybridization (CGH) have proven extremely useful in the identification of unknown chromosomal material.
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[43.] Mmu/Fragment 085 21 - Diskussion
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Duplications or deletions of regions on chromosome 17 have been implicated in a number of genomic disorders in humans (Lupski and Stankiewicz, 2005). Chromosome 17 has the second highest gene content amongst all chromosomes. It harbors several dosage-sensitive genes, including PMP22, PAFAH1B1,YWHAE, RAI1, and NF1, which have been implicated in a number of genomic disorders (Lupski, 2009). Genomic studies have elucidated the mechanisms underlying genomic rearrangements in chromosome 17 and their contribution to the clinical phenotypes.

44. Lupski JR & Stankiewicz P. 2005.Genomic disorders: Molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet 1:e49.

46. Lupski JR. 2009. Genomic disorders ten years on. Genome Med 1:42.

Duplications or deletions of regions on chromosome 17 have been implicated in a number of genomic disorders in humans [Lupski and Stankiewicz, 2005]. Genomic studies have provided us with insight into the complex genomic structure of chromosome 17. This elucidated the framework for our understanding of the mechanisms underlying genomic rearrangements in chromosome 17 and their contribution to the clinical phenotypes.

[page 1102]

Chromosome 17 has the second highest gene content amongst all chromosomes [Zody et al., 2006]. It harbors several dosage-sensitive genes, including PMP22, PAFAH1B1,YWHAE, RAI1, and NF1, which have been implicated in a number of genomic disorders [Lupski, 1998, 2009].


Lupski JR, Stankiewicz P. 2005.Genomic disorders: Molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet 1:e49.

Lupski JR. 2009. Genomic disorders ten years on. Genome Med 1:42.

Lupski JR. 1998. Genomic disorders: Structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14:417.

Zody MC, Garber M, Adams DJ, Sharpe T, Harrow J, Lupski JR, Nicholson C, Searle SM, Wilming L, Young SK, Abouelleil A, Allen NR, BiW,Bloom T, Borowsky ML, Bugalter BE, Butler J, Chang JL, Chen CK, Cook A, Corum B, Cuomo CA, de Jong PJ, DeCaprio D, Dewar K, FitzGerald M, Gilbert J, Gibson R, Gnerre S, Goldstein S, Grafham DV, Grocock R, Hafez N, Hagopian DS, Hart E, Norman CH, Humphray S, Jaffe DB, Jones M, Kamal M, Khodiyar VK, LaButti K, Laird G, Lehoczky J, Liu X, Lokyitsang T, Loveland J, Lui A, Macdonald P, Major JE, Matthews L, Mauceli E, McCarroll SA, Mihalev AH, Mudge J, Nguyen C, Nicol R, O’Leary SB, Osoegawa K, Schwartz DC, Shaw-Smith C, Stankiewicz P, Steward C, Swarbreck D, Venkataraman V, Whittaker CA, Yang X, Zimmer AR, Bradley A, Hubbard T, Birren BW, Rogers J, Lander ES, Nusbaum C. 2006. DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage. Nature 440:1045–1049.

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Genomic rearrangements describe mutational changes that alter genome structure (e.g., duplication, deletion, insertion, and inversion). These are different from the traditional mutation caused by Watson–Crick base pair alterations. Each of these rearrangements, excepting inversions, result in copy number variation (CNV) or change from the usual copy number of two for a given genomic segment or genetic locus of our diploid genome. Genomic rearrangements can represent polymorphisms that are neutral in function, or may produce abnormal phenotypes. The pathological conditions caused by genomic rearrangements are collectively defined as genomic disorders (Lupski 1998 and 2009). Due to the limited resolution of conventional cytogenetic techniques, the majority of genomic disorders were missed in the past, because the genomic rearrangements were not cytogenetically visible. However, high-resolution array comparative genomic hybridization (aCGH) techniques have revolutionized the approach to diagnosis of genomic disorders, and enabled the screen of the entire human genome for CNVs. Genomic rearrangements describe mutational changes that alter genome structure (e.g., duplication, deletion, insertion, and inversion). These are different from the traditional mutation caused by Watson–Crick base pair alterations. Each of these rearrangements, excepting inversions, result in copy number variation (CNV) or change from the usual copy number of two for a given genomic segment or genetic locus of our diploid genome. Genomic rearrangements can represent polymorphisms that are neutral in function, or may produce abnormal phenotypes. The pathological conditions caused by genomic rearrangements are collectively defined as genomic disorders [Lupski, 1998, 2009]. Due to the limited resolution of conventional cytogenetic techniques, the majority of genomic disorders were missed in the past, because the genomic rearrangements were not cytogenetically visible. However, high-resolution array comparative genomic hybridization (aCGH) techniques have revolutionized the approach to diagnosis of genomic disorders, and enabled the screen of the entire human genome for CNVs.
Anmerkungen

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The MURCS association may be attributed to alterations in blastema giving rise to the cervicothoracic somites and the pronephric ducts, the ultimate spatial relationships of which are already determined by the end of the fourth week of fetal development (Duncan 1979). From literature we know that the smallest common deleted region among the deletions overlapping 22q11.2 and associated with MURCS is the most frequent 3 Mb 22q11.2 deletion associated with DiGeorge syndrome (Morcel 2011). This strongly suggests that the MURCS association is an additional component of the 22q11.2 deletion phenotype

7. Duncan PA, Shapiro LR, Stangel JJ, Klein RM, Addonizio JC: The MURCS association: Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia. J Pediatr 1979, 95:399-402.

20. Morcel K. et al. Utero-vaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci. Orphanet Journal of Rare Diseases 2011, 6:9

Type II MRKH or the MURCS association may be attributed to alterations in the blastema giving rise to the cervicothoracic somites and the pronephric ducts, the ultimate spatial relationships of which are already determined by the end of the fourth week of fetal development [21].

[page 7]

The smallest common deleted region among the deletions overlapping 22q11.2

[page 8]

and associated with MRKH type II (MURCS association) is the most frequent ~3 Mb 22q11.2 deletion associated with DGS [76] (Figure 5). This strongly suggests that the MURCS association is an additional component of the 22q11.2 deletion phenotype.


21. Duncan PA, Shapiro LR, Stangel JJ, Klein RM, Addonizio JC: The MURCS association: Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia. J Pediatr 1979, 95:399-402

76. Shaikh TH, Kurahashi H, Saitta SC, O’Hare AM, Hu P, Roe BA, Driscoll DA, McDonald-McGinn DM, Zackai EH, Budarf ML, Emanuel BS: Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 2000, 9:489-501.

Anmerkungen

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Autism spectrum disorders (ASDs), typically apparent by the age of 3 years, encompass a broad range of developmental disorders that are marked by limitations in one of three behavioural/developmental domains: social interaction; language, communication, and imaginative play; and range of interest and activities (Muhle 2004). The ASDs range from phenotypically mild to severe and include autism, atypical autism, Asperger syndrome, and pervasive developmental disorders. The heritability of autism may as high as 90%, making it one of the most heritable [complex disorders.]

55.Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004;113:e472– e486.

Autism spectrum disorders (ASDs) encompass a broad range of developmental disorders that are marked by limitations in one of three behavioral/developmental domains: (1) social interaction; (2) language, communication, and imaginative play; and (3) range of interests and activities.1 The ASDs range from phenotypically mild to severe and include autism, atypical autism, Asperger syndrome, Rett syndrome, and pervasive developmental disorders.2 [...]

[...] Results of twin and family studies have shown that the heritability of autism may be as high as 90%, making it one of the most heritable complex disorders.6


1. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004;113:e472– e486.

2. Sykes NH, Lamb JA. Autism: the quest for the genes. Expert Rev Mol Med 2007;9:1–15.

6. Freitag CM. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry 2007;12:2–22.

Anmerkungen

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Continued on the following page: Mmu/Fragment 087 03

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Decreased expression resulting from a gene deletion causes a phenotype usually similar to that observed with loss-of-function point mutations of a ‘‘dosage-sensitive’’ gene. Increased expression, resulting from gene duplication may convey clinical findings that are different, and sometimes divergent from the deletion phenotype (Bi 2009). Decreased expression resulting from a gene deletion causes a phenotype usually similar to that observed with loss-of-function point mutations, for example, nonsense and frame-shift alleles for a ‘‘dosage-sensitive’’ gene. Increased expression of a dosage-sensitive gene resulting from a gene duplication may convey clinical findings which are different, and sometimes divergent from the deletion phenotype [Potocki et al., 2007; Girirajan et al., 2008; Bi et al., 2009].
Anmerkungen

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Bi et al. (2009) does not contain the parallel text.

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The presence of a CNVs in a coding region usually correlates with changes in the abundance of corresponding transcripts. Absence or excess of the protein product of a dosage sensitive gene may influence cell differentiation or migration and tissue formation early during development. In addition, genomic rearrangements may also be associated with molecular mechanisms other than affecting transcript levels to influence gene dosage and expression. Such complex mechanisms include gene interruption, gene fusion, unmasking a recessive allele or silenced gene, and interruption of regulatory gene-gene and chromosomal interactions (Lupski and Stankiewicz 2005). Even before the completion of the Human Genome Project, the pathogenic significance of gene dosage was realized in several disorders of the central and peripheral nervous system.

44. Lupski JR & Stankiewicz P. 2005.Genomic disorders: Molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet 1:e49.

The presence of a CNV in a coding region usually correlates with changes in the abundance of corresponding transcripts. Absence or excess of the protein product of a dosage sensitive gene may influence cell differentiation or migration and tissue formation early during development. [...]

In addition, genomic rearrangements may also be associated with molecular mechanisms other than affecting transcript levels to influence gene dosage and expression. Such complex mechanisms include gene interruption, gene fusion, unmasking a recessive allele or silenced gene, and interruption of regulatory gene-gene and chromosomal interactions.5 [...]

[...]

[...] Even before the completion of the Human Genome Project, the pathogenic significance of gene dosage was realized in several disorders of the central and peripheral nervous system (CNS, PNS).


5. Lee JA, Lupski JR. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron. 2006;52:103–121.

Anmerkungen

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[49.] Mmu/Fragment 090 01 - Diskussion
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[Functional polymorphisms within COMT and FXII, unmasked by hemizygous] deletions, have also been reported to result in cognitive decline and psychosis in patients with 22q11.2 deletion and reduced activity of coagulation factor 12 in Sotos syndrome respectively (Gothelf 2005, Kurotaki 2005).]

25. Gothelf, D. et al. (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat. Neurosci., 8, 1500–1502.

38. Kurotaki N., et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet. Med., 7, 479–483.

Functional polymorphisms within COMT and FXII, unmasked by hemizygous deletions, have also been reported to result in cognitive decline and psychosis in patients with del22q11.2 and reduced activity of coagulation factor 12 in Sotos syndrome, respectively (88,89).

88. Gothelf, D., Eliez, S., Thompson, T., Hinard, C., Penniman, L., Feinstein, C., Kwon, H., Jin, S., Jo, B., Antonarakis, S.E. et al. (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat. Neurosci., 8, 1500–1502.

89. Kurotaki, N., Shen, J.J., Touyama, M., Kondoh, T., Visser, R., Ozaki, T., Nishimoto, J., Shiihara, T., Uetake, K., Makita, Y. et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet. Med., 7, 479–483.

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[50.] Mmu/Fragment 089 16 - Diskussion
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The highlighted examples demonstrate how gene dosage effects may influence the development of common disorders often characterized by heterogeneous genetic aetiology. The highlighted examples demonstrate how gene dosage effects may influence cell function and development of common disorders often characterized by heterogeneous genetic etiology.
Anmerkungen

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[51.] Mmu/Fragment 089 19 - Diskussion
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Other molecular mechanisms by which rearrangements of the genome may convey or alter a disease phenotype result from how the rearrangement on one chromosome affects or is affected by the allele on the other chromosome at that locus. These include the unmasking of either recessive mutations or functional polymorphisms of the remaining allele when a deletion occurs, and potential transvection effects via deletion of regulatory elements required for communication between alleles (Lupski and Stankiewicz 2005).

44. Lupski JR & Stankiewicz P. 2005.Genomic disorders: Molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet 1:e49.

Other molecular mechanisms by which rearrangements of the genome may convey or alter a disease phenotype result from how the rearrangement on one chromosome affects or is affected by the allele on the other chromosome at that locus (Figure 3E and 3F). These include the unmasking of either recessive mutations (reviewed in [63]) or functional polymorphisms [64] of the remaining allele when a deletion occurs, and potential transvection (communication between alleles on homologous chromosomes) [16,17] effects via deletion of regulatory elements required for communication between alleles.

16. Yan J, Keener VW, Bi W, Walz K, Bradley A, et al. (2004) Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith-Magenis syndrome. Hum Mol Genet 13: 2613–2624.

17. Bi W, Ohyama T, Nakamura H, Yan J, Visvanathan J, et al. (2005) Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome. Hum Mol Genet 14: 983–995.

63. Shaffer LG, Ledbetter DH, Lupski JR (2001) Molecular cytogenetics of contiguous gene syndromes: Mechanisms and consequences. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, et al., editors. The metabolic and molecular bases of inherited diseases. New York: McGraw-Hill. pp. 6077–6096.

64. Kurotaki N, Shen JJ, Touyama M, Kondoh T, Visser R, et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet Med 7: 479–483.

Anmerkungen

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[52.] Mmu/Fragment 089 25 - Diskussion
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Recessive genes reside within the CNV regions, and the chances of finding a recessive mutation along with a microdeletion are rare (frequency of spontaneous mutation x frequency of the deletion event), but plausible. Profound sensorineural hearing loss has been reported in patients with Smith-Magenis syndrome whose deletions unmask the recessive mutation in the myosin (MYO15A) gene located within the 17p11.2 region (Liburd 2001). Functional polymorphisms within COMT and FXII, unmasked by hemizygous [deletions, have also been reported to result in cognitive decline and psychosis in patients with 22q11.2 deletion and reduced activity of coagulation factor 12 in Sotos syndrome respectively (Gothelf 2005, Kurotaki 2005).]

25. Gothelf, D. et al. (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat. Neurosci., 8, 1500–1502.

38. Kurotaki N., et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet. Med., 7, 479–483.

42. Liburd N., et al. (2001) Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith–Magenis syndrome. Hum. Genet., 109, 535–541.

Furthermore, recessive genes reside within the CNV regions, and the chances of finding a recessive mutation along with a microdeletion are rare (frequency of spontaneous mutation x frequency of the deletion event), but plausible (Fig. 3). Profound sensorineural hearing loss has been reported in patients with Smith-Magenis syndrome whose deletions unmask the recessive mutations in the myosin (MYO15A) gene located within the 17p11.2 region (87). Functional polymorphisms within COMT and FXII, unmasked by hemizygous deletions, have also been reported to result in cognitive decline and psychosis in patients with del22q11.2 and reduced activity of coagulation factor 12 in Sotos syndrome, respectively (88,89).

87. Liburd, N., Ghosh, M., Riazuddin, S., Naz, S., Khan, S., Ahmed, Z., Riazuddin, S., Liang, Y., Menon, P.S., Smith, T. et al. (2001) Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith–Magenis syndrome. Hum. Genet., 109, 535–541.

88. Gothelf, D., Eliez, S., Thompson, T., Hinard, C., Penniman, L., Feinstein, C., Kwon, H., Jin, S., Jo, B., Antonarakis, S.E. et al. (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat. Neurosci., 8, 1500–1502.

89. Kurotaki, N., Shen, J.J., Touyama, M., Kondoh, T., Visser, R., Ozaki, T., Nishimoto, J., Shiihara, T., Uetake, K., Makita, Y. et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet. Med., 7, 479–483.

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[53.] Mmu/Fragment 014 18 - Diskussion
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There are several explanations for variable expressivity and clinical heterogeneity in genomic disorders. First, the breakpoints of the events may not be identical. Atypical deletions and duplications involving contiguous dosage-sensitive genes within the region often explained the observed clinical variability in many genomic disorders. VARIABLE EXPRESSIVITY IN GENOMIC DISORDERS

There are several explanations for variable expressivity and clinical heterogeneity in genomic disorders (Fig. 3). First, the breakpoints of the events may not be identical. Atypical deletions and duplications involving contiguous dosage-sensitive genes within the region often explained the observed clinical variability in many genomic disorders.

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[54.] Mmu/Fragment 092 20 - Diskussion
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It is not clear to what extent such genomic changes are responsible for Mendelian or complex disease traits and common traits, or represent only benign polymorphic variation. Furthermore, some phenotypes caused by genomic rearrangements may not present until late adulthood. This age-dependent penetrance confounds the interpretation of genomic copy-number changes.

We know that rearrangements occur throughout the genome, and therefore it is plausible to assume that such rearrangements or CNVs could be associated with inherited or sporadic disease, susceptibility to disease, complex traits, or common benign traits, or could represent polymorphic variation with no apparent phenotypic consequences, depending on whether or not dosage-sensitive genes are affected by the rearrangement.

It is not clear to what extent such genomic changes are responsible for Mendelian or complex disease traits and common traits (including behavioral traits), or represent only benign polymorphic variation. [...] Furthermore, some phenotypes caused by genomic rearrangements (e.g., HNPP) may not present until late adulthood — if at all [5,6]. This age-dependent penetrance confounds the interpretation of genomic copy-number changes. [...]

[...] Nevertheless, it is clear that LCR/NAHR-generated rearrangements occur throughout the genome [1,2], and therefore it is not unreasonable to assume that such rearrangements or CNVs could be associated with inherited or sporadic (de novo rearrangement) disease, susceptibility to disease, complex traits, or common benign traits, or could represent polymorphic variation with no apparent phenotypic consequences (Figure 4), depending on whether or not dosage-sensitive genes are affected by the rearrangement.


1. Lupski JR (1998) Genomic disorders: Structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14: 417–422.

2. Stankiewicz P, Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends Genet 18: 74–82.

5. Lupski JR, Garcia A (2001) Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, et al., editors. The metabolic and molecular bases of inherited diseases, 8th ed. New York: McGraw-Hill. pp. 5759–5788.

6. Lupski JR, Chance PF (2005) Hereditary motor and sensory neuropathies involving altered dosage or mutation of PMP22: The CMT1A duplication and HNPP deletion. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. Philadelphia: Elsevier Science. pp. 1659–1680.

Anmerkungen

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[6. CONCLUSIONS and FUTURE PERSPECTIVES]

The conventional wisdom surrounding genomic disorders posits that they fit several criteria: the deletions/duplications are large, highly penetrant, de novo in the majority of individuals, and associated with a uniform constellation of clinical features (Mefford and Eichler, 2009). Smith-Magenis syndrome, Prader-Willi syndrome, and Williams-Beuren syndrome are examples of such “classic” genomic disorders. In contrast to these “classic” genomic disorders, many of the more recently described recurrent genomic lesions identified in large case–control studies demonstrate apparently diverse phenotypes and are frequently inherited while showing reduced penetrance (Klopocki et al., 2007; Mefford et al., 2008; Sharp et al., 2008).

Several explanations have been proposed for the variable expressivity and clinical heterogeneity in some genomic disorders. First, atypical or variable-sized copy number changes may account for the variable phenotypes in some apparently recurrent lesions. A “two-hit” model has also recently been proposed to account for phenotypic variability. One hit may be sufficient to reach a threshold that results in mild neurodevelopmental deficits, whereas a second hit is necessary for the development of a more severe neurological phenotype. Alternatively, the abnormal phenotype in patients with a heterozygous deletion can result from unmasking of a recessive mutation or functional polymorphism of the remaining allele.


34. Klopocki E, et al. 2007. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia- absent radius syndrome. Am J Hum Genet 80:232–240.

54.Mefford HC, et al. 2008. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 359:1685–1699.

73. Sharp AJ, et al 2008. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40:322–328.

[Page 7]

Discussion

The conventional wisdom surrounding genomic disorders posits that they fit several criteria: the deletions/duplications are large, highly penetrant, de novo in the majority of individuals, and associated with a uniform constellation of clinical features [Mefford and Eichler, 2009]. Smith-Magenis syndrome, Prader-Willi syndrome, and Williams-Beuren syndrome are examples of such “classic” genomic disorders. In contrast to these “classic” genomic disorders, many of the more recently described recurrent genomic lesions identified in large case–control studies demonstrate apparently diverse phenotypes and are frequently inherited while showing reduced penetrance [Ensenauer et al., 2003; Hannes et al., 2008; Klopocki et al., 2007; Mefford et al., 2008; Sharp et al., 2008., Ullmann et al., 2007; Yobb et al., 2005].

[Page 8]

Several explanations have been proposed for the variable expressivity and clinical heterogeneity in some genomic disorders. First, atypical or variable-sized copy number changes may account for the variable phenotypes in some apparently recurrent lesions. [...]

A “two-hit” model has also recently been proposed to account for phenotypic variability; it was first used to describe the recurrent deletion 16p12.1 [Girirajan et al., 2010]. [...] One hit may be sufficient to reach a threshold that results in mild neurodevelopmental deficits, whereas a second hit is necessary for the development of a more severe neurological phenotype, including ID/DD, ASDs, or schizophrenia [Girirajan and Eichler, 2010].

[Page 9]

Alternatively, the abnormal phenotype in patients with a heterozygous deletion of a gene responsible for an autosomal recessive trait can result from unmasking of a recessive mutation or functional polymorphism of the remaining allele [Kurotaki et al., 2005].


Ensenauer RE, Adeyinka A, Flynn HC, Michels VV, Lindor NM, Dawson DB, Thorland EC, Lorentz CP, Goldstein JL, McDonald MT, Smith WE, Simon-Fayard E, Alexander AA, Kulharya AS, Ketterling RP, Clark RD, Jalal SM. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet. 2003; 73:1027–1040. [PubMed: 14526392]

Girirajan S, Eichler EE. Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet. 2010; 19:R176–187. [PubMed: 20807775]

Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, Vives L, Walsh T, McCarthy SE, Baker C, Mefford HC, Kidd JM, Browning SR, Browning BL, Dickel DE, Levy DL, Ballif BC, Platky K, Farber DM, Gowans GC, Wetherbee JJ, Asamoah A, Weaver DD, Mark PR, Dickerson J, Garg BP, Ellingwood SA, Smith R, Banks VC, Smith W, McDonald MT, Hoo JJ, French BN, Hudson C, Johnson JP, Ozmore JR, Moeschler JB, Surti U, Escobar LF, El-Khechen D, Gorski JL, Kussmann J, Salbert B, Lacassie Y, Biser A, McDonald-McGinn DM, Zackai EH, Deardorff MA, Shaikh TH, Haan E, Friend KL, Fichera M, Romano C, Gécz J, DeLisi LE, Sebat J, King MC, Shaffer LG, Eichler EE. A recurrent 16p12.1 microdeletion supports a twohit model for severe developmental delay. Nat Genet. 2010; 42:203–209. [PubMed: 20154674]

Klopocki E, Schulze H, Strauss G, Ott C-E, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, Konig R, Seemanova E, Megarbane A, Ropers H-H, Ullmann R, Horn D, Mundlos S. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet. 2007; 80:232–240. [PubMed: 17236129]

Kurotaki N, Shen JJ, Touyama M, Kondoh T, Visser R, Ozaki T, Nishimoto J, Shiihara T, Uetake K, Makita Y, Harada N, Raskin S, Brown CW, Hoglund P, Okamoto N, Lupski JR. Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet Med. 2005; 7:479–483. [PubMed: 16170239]

Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008; 359:1685–1699. [PubMed: 18784092]

Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, Stevenson RE, Schroer RJ, Schroer RJ, Novara F, De Gregori M, Ciccone R, Broomer A, Casuga I, Wang Y, Xiao C, Barbacioru C, Gimelli G, Bernardina BD, Torniero C, Giorda R, Regan R, Murday V, Mansour S, Fichera M, Castiglia L, Failla P, Ventura M, Jiang Z, Cooper GM, Knight SJ, Romano C, Zuffardi O, Chen C, Schwartz CE, Eichler EE. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet. 2008; 40:322–328. [PubMed: 18278044]

Ullmann R, Turner G, Kirchhoff M, Chen W, Tonge B, Rosenberg C, Field M, Vianna-Morgante AM, Christie L, Krepischi-Santos AC, Banna L, Brereton AV, Hill A, Bisgaard AM, Muller I, Hultschig C, Erdogan F, Wieczorek G, Ropers HH. ArrayCGHidentifiesreciprocal16p13.1duplicationsanddeletionsthatpredispose to autism and/or mental retardation. Hum Mutat. 2007; 28:674–682. [PubMed: 17480035]

Yobb TM, Somerville MJ, Willatt L, Firth HV, Harrison K, MacKenzie J, Gallo N, Morrow BE, Shaffer LG, Babcock M, Chernos J, Bernier F, Sprysak K, Christiansen J, Haase S, Elyas B, Lilley M, Bamforth S, McDermid HE. Microduplication and triplication of 22q11.2: a highly variable syndrome. Am J Hum Genet. 2005; 76:865–876. [PubMed: 15800846]

Anmerkungen

The first part of the Conclusions has been copied verbatim from the paper Stankiewicz et al 2012, which according to her own list of references has been known to MMu.

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[56.] Mmu/Fragment 058 02 - Diskussion
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Although clinical genetic laboratories are familiar with recurrent copy-number changes mediated by segmental duplication architecture, population studies suggest that the vast majority of copy-number variation is not recurrent (Itsara 2009). Even if array-CGH offers the sensitivity of high-resolution genome-wide detection of clinically significant CNVs, the additional challenge of interesting variants of uncertain clinical significance can impose a burden on clinicians and laboratories (Vos 2009).

13. Itsara, A., Cooper, G.M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R.M., Myers, R.M., Ridker, P.M., Chasman, D.I., et al. (2009). Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84, 148–161.

25. Vos, J., van Asperen, C.J., Wijnen, J.T., Stiggelbout, A.M., and Tibben, A. (2009). Disentangling the Babylonian speech confusion in genetic counseling: an analysis of the reliability and validity of the nomenclature for BRCA1/2 DNA-test results other than pathogenic. Genet. Med. 11, 742–749.

Although clinical genetic laboratories are familiar with recurrent copy-number changes mediated by segmental duplication architecture, population studies suggest that the vast majority of copy-number variation is not recurrent.11 Determining the clinical significance of variants identified by CMA can be challenging. Although CMA offers the sensitivity of high-resolution genome-wide detection of clinically significant copy-number variants (CNVs), the additional challenge of interpreting variants of uncertain clinical significance (VOUS), the preferred terminology based on a recent study of variant terminology, can impose a burden on clinicians and laboratories.12

11. Itsara, A., Cooper, G.M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R.M., Myers, R.M., Ridker, P.M., Chasman, D.I., et al. (2009). Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84, 148–161.

12. Vos, J., van Asperen, C.J., Wijnen, J.T., Stiggelbout, A.M., and Tibben, A. (2009). Disentangling the Babylonian speech confusion in genetic counseling: an analysis of the reliability and validity of the nomenclature for BRCA1/2 DNA-test results other than pathogenic. Genet. Med. 11, 742–749.

Anmerkungen

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"interpreting" has changed to "interesting".

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[57.] Mmu/Fragment 057 17 - Diskussion
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Bremer et al 2010, Fragment, Gesichtet, KomplettPlagiat, Mmu, SMWFragment, Schutzlevel sysop

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Until recently, karyotyping has been the standard method for the detection of cytogenetic aberrations in patients with developmental disorders. The development of whole-genome screening methodologies for the detection of CNVs, such as array-CGH, provides a much higher resolution than karyotyping leading to the identification of novel microdeletion and microduplication syndromes, such as deletions and duplications in chromosome band 15q13.2q13.3, 16p11.2, and 17p11.2, often associated with an autism phenotype (Ballif et al., 2007; Potocki et al., 2007; Weiss et al., 2008; Miller et al., 2009).

3. Ballif BC, Hornor SA, Jenkins E, Madan-Khetarpal S, Surti U, Jackson KE, Asamoah A, Brock PL, Gowans GC, Conway RL, et al. 2007. Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat Genet 39(9): 1071–1073.

16. Miller DT, Shen Y, Weiss LA, Korn J, Anselm I, Bridgemohan C, Cox GF, Dickinson H, Gentile J, Harris DJ, et al. 2009. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 46(4): 242–248.

18. Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, Glaze D, Krull K, Lee JA, Lewis RA, et al. 2007. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 80(4): 633–649.

26. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, et al. 2008. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358(7): 667–675.

Until recently, karyotyping has been the standard method for the detection of cytogenetic aberrations in patients with developmental disorders. The development of whole-genome screening methodologies for the detection of CNVs, such as array-based comparative genomic hybridization (array-CGH), provides a much higher resolution than karyotyping leading to the identification of novel microdeletion- and microduplication syndromes, such as deletions and duplications in chromosome band 15q13.2q13.3, 16p11.2, and 17p11.2, often associated with an autism phenotype [Ballif et al., 2007; Potocki et al., 2007; Weiss et al., 2008; Miller et al., 2009].

Ballif BC, Hornor SA, Jenkins E, Madan-Khetarpal S, Surti U, Jackson KE, Asamoah A, Brock PL, Gowans GC, Conway RL, et al. 2007. Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat Genet 39(9):1071–1073.

Miller DT, Shen Y, Weiss LA, Korn J, Anselm I, Bridgemohan C, Cox GF, Dickinson H, Gentile J, Harris DJ, et al. 2009. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 46(4):242–248

Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, Glaze D, Krull K, Lee JA, Lewis RA, et al. 2007. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 80(4):633–649.

Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, et al. 2008. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358(7):667–675.

Anmerkungen

Nothing has been marked as a citation; the source is not given.

Though the source has a number of co-authors, M. M. is not one of them. In fact, Bremer et al 2010 presents results from a Stockholm (Sweden) based research team.

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(Graf Isolan), Hindemith

[58.] Mmu/Fragment 012 09 - Diskussion
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Some of these aberrations are apparently benign CNVs and are usually inherited from a parent (Lee 2007). If identical alterations are found either in one of the unaffected parents, or in independent normal controls, they most probably have no direct phenotypic

consequences; however, low penetrance and variable expressivity of the phenotype may complicate the analysis and genetic counseling. Currently, the publicly available CNV databases assist in making decisions about the clinical significance of imbalances detected by microarrays. Examples of such databases are the Database of Genomic Variants (http://projects.tcag.ca/variation). When determined as de novo in origin genomic imbalances are considered more likely pathological (Tyson 2005). This can be further supported if the implicated region contains gene(s) with functions compatible with the abnormal clinical findings or previously described patients with a similar genomic imbalance and a similar phenotype. The de novo occurrence of copy number alteration is, however, not an absolute evidence of its pathogenicity and caution must be exercised for possible non paternity.


40. Lee JA, Carvalho CM, Lupski JR. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007 Dec 28;131(7):1235-47.

41. Lee, C., Iafrate A.J., and Brothman A.R., Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet, 2007. 39(7 Suppl): p. S48-54.

79. Tyson C, et al. Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH. Am J Med Genet A. 2005 Dec 15;139(3):173-85.

are apparently benign CNVs and are usually inherited from a parent [10]. If identical alterations are found either in one of the unaffected parents, or in independent normal controls, they most probably have no direct phenotypic consequences; however, low penetrance and variable expressivity of the phenotype may complicate the analysis and genetic counseling. Currently, the publicly available CNV databases assist in making decisions about the clinical significance of imbalances detected by microarrays. Examples of such databases are the Database of Genomic Variants (http://www.projects.tcag.ca/variation/, http://www.genome.ucsc.edu/ and http://www.sanger.ac.uk/PostGenomics/decipher/). Investigations of the parents and additional family members may often be necessary to interpret and clarify these results. The elimination of such regions from the new generations of microarray can improve the specificity and subsequently facilitate the genetic counseling.

When determined as de novo in origin genomic imbalances are considered pathogenic. This can be further supported if the implicated region contains gene(s) with functions compatible with the abnormal clinical findings or previously described patients with a similar genomic imbalance and a similar phenotype. The de novo occurrence of copy number alteration is, however, not an absolute evidence of its pathogenicity and caution must be exercised for possible nonpaternity.


10 Lee, C. et al. (2007) Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat. Genet. 39, S48–54

Anmerkungen

Nothing has been marked as a citation. The source is not given.

"(Lee 2007)" cannot be uniquely resolved by the references given by Mmu.

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(Graf Isolan), SleepyHollow02

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1.3.1 Discovering new syndromes

Deletion and duplication syndromes represent recurrent chromosomal abnormalities that are associated with distinct phenotypes. These microdeletions/microduplications often occur between low copy repeats (LCRs) and are commonly because of non-allelic homologous recombination (NAHR) events (Lupski 1998). The detection of a de novo genomic imbalance in a single patient does not prove pathogenicity. Only the identification of similar genomic imbalances with a recognizable phenotype can help clarify the role of these genomic changes in causing the specific clinical features and will ultimately define a genetic syndrome.


45. Lupski JR. 1998. Genomic disorders: Structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14:417.

Identification of new syndromes by aCGH

Deletion and duplication syndromes represent recurrent chromosomal abnormalities that are associated with distinct phenotypes. These microdeletions/microduplications often occur between low copy repeats (LCRs) and are commonly because of nonallelic homologous recombination (NAHR) events [37]. The detection of a de novo genomic imbalance in a single patient does not prove pathogenicity. Only the identification of similar genomic imbalances with a recognizable phenotype can help clarify the role of these genomic changes in causing the specific clinical features and will ultimately define a genetic syndrome.


37 Lupski, J.R. (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422

Anmerkungen

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(Graf Isolan), SleepyHollow02

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The higher resolution and throughput with possibilities for automation, robustness, simplicity, high reproducibility and precise mapping of aberrations are the most significant advantages of aCGH over cytogenetic methods. In addition, there is no need for cell culture, making the turn around time shorter than in cytogenetic methods. As with other clinical diagnostic methods, there are limitations in aCGH technology. aCGH is not able to identify balanced rearrangements such as translocations and inversions and low-level mosaicism for unbalanced numeric or structural rearrangements.

1.2 Array – CGH Methodologies

In aCGH, equal amounts of labelled genomic DNA from a test and a reference sample are co-hybridized to an array containing the DNA targets. Genomic DNA of the patient and control are differentially labelled with Cyanine 3 (Cy3) and Cyanine 5 (Cy5). The slides are scanned into image files using a microarray scanner. The spot intensities are measured and the image files are quantified using feature extraction software, and text file outputs from the quantitative analyses are imported into software programs for copy number analysis (Fig.2) (Cheung 2005, Lu 2007). The resulting ratio of the fluorescence intensities is proportional to the ratio of the copy numbers of DNA sequences in the test and reference genomes.


17. Cheung S.W. et al. (2005) Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet. Med. 7, 422–432

43. Lu, X. et al. (2007) Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases. PLoS ONE 2, e327

[Page 761]

aCGH methodology

In aCGH, equal amounts of labeled genomic DNA from a test and a reference sample are cohybridized to an array containing the DNA targets. [...] Genomic DNA of the patient and control are differen-

[Page 762]

tially labeled with Cyanine 3 (Cy3) and Cyanine 5 (Cy5) (Fig. 2a). [...] The spot intensities are measured (Fig. 2c) and the image files are quantified using feature extraction software, and text file outputs from the quantitative analyses are imported into software programs for copy number analysis (Fig. 2d) [4,9]. The resulting ratio of the fluorescence intensities is proportional to the ratio of the copy numbers of DNA sequences in the test and reference genomes.


FIGURE 2

[...] (b) The slides are scanned into image files using a specific microarray scanner.

[Page 763]

The advantages and limitations of diagnostic aCGH

The higher resolution and throughput with possibilities for automation, robustness, simplicity, high reproducibility and precise mapping of aberrations are the most significant advantages of aCGH over cytogenetic methods. In addition, there is no need for cell culture, making the turn around time shorter than in cytogenetic methods. [...]

As with other clinical diagnostic methods, there are limitations in aCGH technology. aCGH is not able to identify balanced rearrangements such as translocations and inversions.


4 Cheung, S.W. et al. (2005) Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet. Med. 7, 422–432

9 Lu, X. et al. (2007) Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases. PLoS ONE 2, e327

Anmerkungen

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Sichter
(Graf Isolan), SleepyHollow02

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