X-linked mental retardation: a comprehensive molecular screen of 47 candidate genes from a 7.4 Mb interval in Xp11

Abstract

About 30% of the mutations causing nonsyndromic X-linked mental retardation (MRX) are thought to be located in Xp11 and in the pericentromeric region, with a particular clustering of gene defects in a 7.4 Mb interval flanked by the genes ELK1 and ALAS2. To search for these mutations, 47 brain-expressed candidate genes located in this interval have been screened for mutations in up to 22 mental retardation (MR) families linked to this region. In total, we have identified 57 sequence variants in exons and splice sites of 27 genes. Based on these data, four novel MR genes were identified, but most of the sequence variants observed during this study have not yet been described. The purpose of this article is to present a comprehensive overview of this work and its outcome. It describes all sequence variants detected in 548 exons and their flanking sequences, including disease-causing mutations as well as possibly relevant polymorphic and silent sequence changes. We show that many of the studied genes are unlikely to play a major role in MRX. This information will help to avoid duplication of efforts in the ongoing endeavor to unravel the molecular causes of MRX.

DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

“…A more direct link between DIA1R and XLMR comes from two independent studies, where point mutations in DIA1R were implicated in XLMR [60], [122]. It should be noted that any ASD-like symptoms were not commented on in either of these studies, and may not have been evaluated or specifically ruled-out.…”

“…It should be noted that any ASD-like symptoms were not commented on in either of these studies, and may not have been evaluated or specifically ruled-out. In the first study, a mutation affecting the DIA1R signal peptide (a change of serine at position 24 to proline or ‘S24P’, using single amino acid abbreviations) was reported in a single XLMR patient, while the same mutation was absent in controls [122]. Our analyses reveal that the mutant DIA1R gene product (DIA1R-S24P) is still expected to have a functional signal peptide, but the mutation is predicted to change the signal peptide cleavage site (data not shown).…”

MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression

“…10 Sequencing reactions were then carried out for patient DNAs, which showed abnormal elution profiles in the DHPLC analysis.…”

The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability

“…Nine new genes implicated in XLID were reported, including the gene encoding the presynaptic protein CASK. Earlier, smaller-scale sequencing efforts were also performed, for instance, the screening of 47 X-chromosomal genes within a 7.4-Mb region of Xp11 and selected based on brain expression profile in 22 XLID families (Jensen et al 2007). This study reported four new genes for XLID; however, a microarray hybridization approach was used for mutation screening rather than Sanger sequencing, but still not a massively parallel sequencing approach that would be considered as "next-generation.…”