Genetic analysis of the postsynaptic transmembrane X-linked neuroligin 3 gene in autism

Abstract

Autism is a complex neurodevelopmental disorder, the prevalence of which has increased drastically in India in recent years. Neuroligin is a type I transmembrane protein that plays a crucial role in synaptogenesis. Alterations in synaptic genes are most commonly implicated in autism and other cognitive disorders. The present study investigated the neuroligin 3 gene in the Indian autistic population by sequencing and in silico pathogenicity prediction of molecular changes. In total, 108 clinically described individuals with autism were included from the North Karnataka region of India, along with 150 age-, sex-, and ethnicity-matched healthy controls. Genomic DNA was extracted from peripheral blood, and exonic regions were sequenced. The functional and structural effects of variants of the neuroligin 3 protein were predicted. One coding sequence variant (a missense variant) and four non-coding variants (two 5'-untranslated region [UTR] variants and two 3'-UTR variants) were recorded. The novel missense variant was found in 25% of the autistic population. The C/C genotype of c.551T>C was significantly more common in autistic children than in controls (p = 0.001), and a significantly increased risk of autism (24.7-fold) was associated with this genotype (p = 0.001). The missense variant showed pathogenic effects and high evolutionary conservation over the functions of the neuroligin 3 protein. In the present study, we reported a novel missense variant, V184A, which causes abnormal neuroligin 3 and was found with high frequency in the Indian autistic population. Therefore, neuroligin is a candidate gene for future molecular investigations and functional analysis in the Indian autistic population.

Sex-Related Changes in the Clinical, Genetic, Electrophysiological, Connectivity, and Molecular Presentations of ASD: A Comparison between Human and Animal Models of ASD with Reference to Our Data

“…Several investigators have attempted to explain the male predominance of ASD by sex-specific genetic changes in single-nucleotide polymorphisms (SNPs), single-nucleotide variants (SNVs), copy-number variants (CNVs), and different sex-biased proteins [ 22 , 23 , 149 , 150 , 151 , 152 ]. Mutations in specific genes, particularly genes linked to X or Y chromosomes, have been implicated in male vulnerability to ASD [ 44 , 153 , 154 ]. For example, Nguyen et al [ 44 ] suggested that the X-linked cell adhesion molecule NLGN4X, a mutation in which is known to be associated with ASD or intellectual disabilities, may contribute to the male bias in ASD, because the Y chromosome variant, NLGN4Y , cannot compensate for the functional deficits created by the X-linked mutation.…”