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New insights into the pathogenic mechanisms associated with CNVs: duplication of 17p13.3, mirror effect in 16p11.2 and recessive phenotype in 22q11.22

von Dott. Mafalda Mucciolo

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Statistik und Sichtungsnachweis dieser Seite findet sich am Artikelende
[1.] Mmu/Fragment 092 01 - Diskussion
Zuletzt bearbeitet: 2014-11-19 09:57:10 Singulus
Fragment, Gesichtet, KomplettPlagiat, Mmu, SMWFragment, Schutzlevel sysop, Stankiewicz et al 2012

Typus
KomplettPlagiat
Bearbeiter
Graf Isolan
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 92, Zeilen: 1-19
Quelle: Stankiewicz et al 2012
Seite(n): 7, 8, 9 (Author manuscript), Zeilen: 7:10 ff; 8:7-10.20-21.26-29; 9:11-14
[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.

Sichter
(Graf Isolan), SleepyHollow02

[2.] Mmu/Fragment 092 20 - Diskussion
Zuletzt bearbeitet: 2014-11-19 10:00:59 Singulus
Fragment, Gesichtet, Lupski and Stankiewicz 2005, Mmu, SMWFragment, Schutzlevel sysop, Verschleierung

Typus
Verschleierung
Bearbeiter
Hindemith
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 92, Zeilen: 20-30
Quelle: Lupski and Stankiewicz 2005
Seite(n): 631, Zeilen: l.col: last sentence
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

The source is not mentioned here.

Sichter
(Hindemith), SleepyHollow02


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