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

Abstract

Mental Retardation Consortium 8X-linked mental retardation (XLMR) is a common, clinically complex and genetically heterogeneous disease arising from many mutations along the X chromosome. Although research during the past decade has identified 490 XLMR genes, many more remain uncharacterized. In this study, copy-number variations (CNVs) were screened in individuals with MR from 144 families by array-based comparative genomic hybridization (aCGH) using a bacterial artificial chromosome-based X-tiling array. Candidate pathogenic CNVs (pCNVs) were detected in 10 families (6.9%). Five of the families had pCNVs involving known XLMR genes, duplication of Xq28 containing MECP2 in three families, duplication of Xp11.22-p11.23 containing FTSJ1 and PQBP1 in one family, and deletion of Xp11.22 bearing SHROOM4 in one family. New candidate pCNVs were detected in five families as follows: identical complex pCNVs involved in dup(X)(p22.2) and dup(X)(p21.3) containing part of REPS2, NHS and IL1RAPL1 in two unrelated families, duplication of Xp22.2 including part of FRMPD4, duplication of Xq21.1 including HDX and deletion of Xq24 noncoding region in one family, respectively. Both parents and only mother samples were available in six and three families, respectively, and pCNVs were inherited from each of their mothers in those families other than a family of the proband with deletion of SHROOM4. This study should help to identify the novel XLMR genes and mechanisms leading to MR and reveal the clinical conditions and genomic background of XLMR.

A family of oculofaciocardiodental syndrome (OFCD) with a novel BCOR mutation and genomic rearrangements involving NHS

“…It is noteworthy that congenital cataract and dental abnormalities were not pointed out in all the members (males and carrier females). 23 Thus, it is unlikely that the genomic rearrangement involving NHS causes congenital cataract and dental abnormalities as found in our family.…”

“…23 Most carrier females of IL1RAPL1 mutations and the carrier mother of the microduplication involving IL1RAPL1 showed normal intelligence. [23][24][25] In this study, one of the three affected females (MC18) had learning difficulties at school, which could be mild presentation of MR. As 18% of patients with BCOR mutations showed MR, 6 it is reasonable that the BCOR mutation, rather than IL1RAPL1 rearrangement, causes mild MR in MC18. Skewed and random X-inactivation in the mother (MC17b) and the elder daughter (MC17) was confirmed, respectively, in this family.…”

“…Recently, Honda et al 23 reported two unrelated X-linked mental retardation Japanese families, which possessed the similar duplication found in our Korean family: the 737-kb duplication at Xp22.2, which contains a part of REPS2 and NHS, and the 100-kb duplication at Xp21.3, which contains a part of IL1RAPL1. In their report, fluorescent in situ hybridization analysis revealed that the clone RP11-438J7, which entirely covered the duplication at Xp21.3, demonstrated two distinct signals at Xp in metaphases, suggesting that the duplication at Xp21.3 was inserted separately from the original site.…”

Modify or die? - RNA modification defects in metazoans

“…97,98 It was linked to nonsyndromic X-linked ID but also to general mental performance. [99][100][101][102][103][104][105] Most of the mutations described so far result in a loss-of-function of the protein, either by impairing the critical SAM-binding domain of the protein or by degradation of the mutant mRNA. 99,101 There are no morphological brain phenotypes in patients.…”

Commentary on ‘Identification of a microdeletion at Xp22.13 in a Taiwanese family presenting with Nance–Horan syndrome’

“…They found novel copy-number aberrations and suggested that the results of X-tiling array are useful for the identification of cryptic copy-number aberrations containing novel genes responsible for diseases such as congenital disorders and X-linked MR. Recently, Honda et al 4 screened copy-number variations (CNVs) in individuals with MR from 144 families by array CGH using a bacterial artificial chromosome-based X-tiling array. They detected 10 (6.9%) pathogenic CNVs.…”