Copy-Number Variations Measured by Single-Nucleotide–Polymorphism Oligonucleotide Arrays in Patients with Mental Retardation

Abstract

Whole-genome analysis using high-density single-nucleotide-polymorphism oligonucleotide arrays allows identification of microdeletions, microduplications, and uniparental disomies. We studied 67 children with unexplained mental retardation with normal karyotypes, as assessed by G-banded chromosome analyses. Their DNAs were analyzed with Affymetrix 100K arrays. We detected 11 copy-number variations that most likely are causative of mental retardation, because they either arose de novo (9 cases) and/or overlapped with known microdeletions (2 cases). The eight deletions and three duplications varied in size from 200 kb to 7.5 Mb. Of the 11 copy-number variations, 5 were flanked by low-copy repeats. Two of those, on chromosomes 15q25.2 and Xp22.31, have not been described before and have a high probability of being causative of new deletion and duplication syndromes, respectively. In one patient, we found a deletion affecting only a single gene, MBD5, which codes for the methyl-CpG-binding domain protein 5. In addition to the 67 children, we investigated 4 mentally retarded children with apparent balanced translocations and detected four deletions at breakpoint regions ranging in size from 1.1 to 14 Mb.

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

“…In this study, we report a mentally retarded sibpair with a deletion of the non-coding region of MBD5, adding additional evidence to MBD5 as an MR gene. However, except for a full everted lower lip, both the patient reported by Wagenstaller et al 15 and sibpair 8 did not show other characteristics such as a coarse face, microcephaly, genital abnormalities, a broad-based/ataxic gait and a disturbed sleep pattern, features frequently noted in the remainder of the 2q23.1 deletion cohort. This suggests that the full range of clinical features of 2q23.1 deletion patients is because of contiguous gene deletions, rather than of MBD5 alone.…”

“…This suggests that the full range of clinical features of 2q23.1 deletion patients is because of contiguous gene deletions, rather than of MBD5 alone. Except for the patient reported by Wagenstaller et al 15 and sibpair 8a and 8b, all patients had a deletion also including the EPC2 gene. Interestingly, two patients (case 1 Jaillard et al 14 and patient 7) had a deletion including MBD5 and EPC2 only.…”

“…24 Interestingly, several 2q23.1 deletion patients were tested for Rett's syndrome. Convincing evidence that haploinsufficiency of MBD5 leads to MR was reported by Wagenstaller et al, 15 who described a mentally retarded male with seizures, who had an intragenic MBD5 deletion extending from the last exon in the non-coding region until exon 7 of the regular isoform. They also reported missense variants in MBD5 in four MR patients, of which the clinical implications remain unknown.…”

“…10,11 In recent years, six submicroscopic deletions comprising chromosome band 2q23.1 have been reported. [12][13][14][15][16][17] Unlike deletions mediated by a nonallelic homologous recombination, these deletions did not have common break points. Nevertheless, except for one case, all deletions did show a common region of overlap in the 2q23.1 region, including two candidate genes, EPC2 and MBD5.…”

High-resolution SNP arrays in mental retardation diagnostics: how much do we gain?

“…The duplication was because of a nonhomologous allelic recombination event among members of the VCX/Y gene family flanking the rearranged segment. The reciprocal deletion of this genomic segment is associated with 80-90% of X-linked icthyosis/MR cases 32 and this duplication was reported in a child with MR, 28 although its pathogenicity has not been definitely proved. 33 Microarray analysis showed that chromosome anomalies detected by standard and molecular cytogenetic techniques may uncover more complex rearrangements resolved by CNV studies.…”