Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability

Abstract

Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next-generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies in both developed and developing countries. Although intellectual disability arises due to diverse causes, a substantial proportion is caused by genomic alterations. Studies have identified causal XLID genomic alterations in more than 100 protein-coding genes located on the X-chromosome. However, the causes for a substantial number of intellectual disability and associated phenotypes still remain unknown. Identification of causative genes and novel mutations will help in early diagnosis as well as genetic counseling of families. Advent of next-generation sequencing methods has accelerated the discovery of new genes involved in mental health disorders. In this study, we analyzed the exomes of three families from India with nonsyndromic XLID comprising seven affected individuals. The affected individuals had varying degrees of intellectual disability, microcephaly, and delayed motor and language milestones. We identified potential causal variants in three XLID genes, including PAK3 (V294M), CASK (complex structural variant), and MECP2 (P354T). Our findings reported in this study extend the spectrum of mutations and phenotypes associated with XLID, and calls for further studies of intellectual disability and mental health disorders with use of next-generation sequencing technologies.

microRNA mir-598-3p mediates susceptibility to stress enhancement of remote fear memory

“…Pak3 interacts directly with Rho GTPases to regulate actin dynamics driving rapid cytoskeletal reorganization in the adult brain (Ramakers 2002). It is most commonly associated with intellectual disability (Muthusamy et al 2017) and inactivation of Pak3 in the forebrain is associated with impaired spatial memory in the Morris Water Maze and contextual FC, while sparing cued FC memory (Hayashi et al 2004). This is interesting, given that our results suggest lower levels of Pak3 are associated with enhanced memory following a stressor, rather than impaired memory, and suggests that a background of stress might alter endogenous levels of Pak3.…”

An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase

“…Since X-linked genes were shown to be expressed more abundantly in the brain than in any other tissue [10], the X chromosome has a disproportionately higher number of genes implicated in mental ability compared with other chromosomes [11,12]. Indeed, aberrations in at least 140 genes located on the X chromosome were found to cause X-linked intellectual disability (XLID) [13][14][15][16], although several candidate genes remain controversial [13].…”

Novel PAK3 gene missense variant associated with two Chinese siblings with intellectual disability: a case report

“…Twelve of them were located in the KD, and two were in the PBD/AID. Currently, only 1 deletion in exon 6-18 has been reported, which covers the major area of the PBD/AID and all of the KD [2,[8][9][10][11][12][13][14][15][16][17][18][19][20] (Table 2, Fig. 2).…”