X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

Abstract

Background: Aproximately 5-10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects.Results: Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%). Conclusion:This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

“…If the same CNV was segregated into cases of MR in the same family, it was considered a candidate for a pCNV, although CNVs observed in unaffected females in the same family or sporadic type were not excluded. Consistent with previous reports (5/108¼4.6% 13 or 8/54¼14.8% 14 ), putative MR-associated pCNVs were detected in 10 families (6.9%, Table 1; Figure 2). The CNVs detected in five families contained known XLMR genes, whereas five candidate pCNVs seemed to be novel, although their pathogenic significance will need to be determined.…”

“…22 DISCUSSION A duplication at Xq28 containing MECP2 is one of the most common genomic rearrangements in neurodevelopmentally delayed male. 15 In this study, the duplication at Xq28 involving MECP2 was detected in Japanese patients at high frequency (3/144¼2.1%) compared with reported cases in Western countries (1/108¼0.9% 13 or 1/54¼1.9% 14 ). The patients manifested several common phenotypes such as severe MR, muscular hypotonia, absence of speech and recurrent respiratory infections as reported.…”

Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism

“…12,19,20 Finally, the growing number of small chromosomal rearrangements (microdeletion, microduplication) involving one or several genes as identified by array-CGH also suggests that copy number changes are important in XLMR. 5,6,21,22 Among the last new genes found mutated in XLMR, the UPF3B gene has been involved in specific and nonspecific MR with or without autism in 4 of 250 tested families. 9 We further analyzed the coding sequence of this gene in the panel of the EuroMRX consortium (372 tested families) as well as in 25 patients diagnosed with Lujan-Fryns, based on the finding of UPF3B mutations in affected individuals of Lujan-Fryns syndrome families.…”

Coffin–Lowry syndrome

“…14 The coding region of this gene is split into 22 exons and encodes a serine/threonine kinase, RSK2 (ribosomal S6 kinase 2). 15 The RPS6KA3 gene is subject to strong allelic heterogeneity with over 140 distinct inactivating mutations that have so far been [16][17][18] In addition, a de novo insertion of a 5¢-truncated LINE-1 element was documented in one family. 19 RSK2 mutations invariably cause a reduction or loss of RSK2 kinase activity.…”