(mentions CMT 1A) Genomic duplication resulting in increased copy number of gene

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J Med Genet. 2008 Dec 3.

Genomic duplication resulting in increased copy number of genes

encoding the sister chromatid cohesion complex conveys clinical

consequences distinct from Cornelia de Lange.

Yan J, Zhang F, Brundage E, Scheuerle A, Lanpher B, kson RP,

Powis Z, HB, Trapane PL, Stachiw-Hietpas D, Keppler-Noreuil

KM, Lalani SR, Sahoo T, Chinault AC, Patel A, Cheung SW, Lupski JR.

Baylor College of Medicine, United States.

Cornelia de Lange Syndrome (CdLS) is a multisystem congenital anomaly

disorder. Heterozygous point mutations in three genes (NIPBL, SMC3

and SMC1A), encoding components of the sister chromatid cohesion

apparatus, are responsible for ~ 50-60% of CdLS cases. Recent studies

have revealed a high degree of genomic rearrangements (e.g. deletions

and duplications) in the human genome, which result in gene copy

number variations (CNV).

CNVs have been associated with a wide range of both Mendelian and

complex traits including disease phenotypes such as Charcot-Marie-

Tooth type 1A, Pelizaeus-Merzbacher, Parkinson, Alzheimer, autism and

schizophrenia. Increased versus decreased copy number of the same

gene can potentially cause either similar or different clinical

features. We identified duplications on chromosomes 5 or X using

genome wide array Comparative Genomic Hybridization (aCGH).

The duplicated regions contain either the NIPBL or the SMC1A genes.

Junction sequences analyses revealed the involvement of three genomic

rearrangement mechanisms. The patients share some common features

including mental retardation, developmental delay, sleep

abnormalities, and crainofacial and limb defects. The systems

affected are the same as in CdLS, but clinical manifestations are

distinct from CdLS; particularly the absence of the CdLS facial

gestalt.

Our results confirm the notion that duplication CNV of genes can be a

common mechanism for human genetic diseases. Defining the clinical

consequences for a specific gene dosage alteration represents a

new " reverse genomics " trend in medical genetics that is reciprocal

to the traditional approach of delineation of the common clinical

phenotype preceding the discovery of the genetic etiology.