Detection of genomic copy number changes in patients with idiopathic mental retardation by high-resolution X-array-CGH: important role for increased gene dosage of XLMR genes.

Hum Mutat 2007 Oct;28(10):1034-42

Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium.

A tiling X-chromosome-specific genomic array with a theoretical resolution of 80 kb was developed to screen patients with idiopathic mental retardation (MR) for submicroscopic copy number differences. Four patients with aberrations previously detected at lower resolution were first analyzed. This facilitated delineation of the location and extent of the aberration at high resolution and subsequently, more precise genotype-phenotype analyses. A cohort of 108 patients was screened, 57 of which were suspected of X-linked mental retardation (XLMR), 26 were probands of brother pairs, and 25 were sporadic cases. A total of 15 copy number changes in 14 patients (13%) were detected, which included two deletions and 13 duplications ranging from 0.1 to 2.7 Mb. The aberrations are associated with the phenotype in five patients (4.6%), based on the following criteria: de novo aberration; involvement of a known or candidate X-linked nonsyndromic(syndromic) MR (MRX(S)) gene; segregation with the disease in the family; absence in control individuals; and skewed X-inactivation in carrier females. These include deletions that contain the MRX(S) genes CDKL5, OPHN1, and CASK, and duplications harboring CDKL5, NXF5, MECP2, and GDI1. In addition, seven imbalances were apparent novel polymorphic regions because they do not fulfill the proposed criteria. Taken together, our data strongly suggest that not only deletions but also duplications on the X chromosome contribute to the phenotype more often than expected, supporting the increased gene dosage mechanism for deregulation of normal cognitive development.

Download full-text PDF

Source
http://doi.wiley.com/10.1002/humu.20564
Publisher Site
http://dx.doi.org/10.1002/humu.20564DOI Listing
October 2007
18 Reads

Publication Analysis

Top Keywords

copy number
12
mental retardation
12
deletions duplications
8
patients idiopathic
8
number changes
8
increased gene
8
gene dosage
8
idiopathic mental
8
changes patients
8
patients
6
associated phenotype
4
criteria novo
4
novo aberration
4
based criteria
4
phenotype patients
4
aberration involvement
4
46% based
4
patients 46%
4
x-linked nonsyndromicsyndromic
4
segregation disease
4

References

(Supplied by CrossRef)
Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation
Allen et al.
Am J Hum Genet 1992
Diagnostic genome profiling in mental retardation
de Vries et al.
Am J Hum Genet 2005

Similar Publications