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

Suyamindra S Kulkarni,Kusal K Das,Pramod B Gai,Smita Hegde,Aditya Pandurangi,Rajat Hegde

doi:10.5808/gi.21029

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.

Highlights

Autism (MIM 209850) is a complex neurodevelopmental disorder that is characterised by impaired verbal and nonverbal communication and social interaction, accompanied by restricted and stereotyped behavior [1,2]
Neuroligin, a postsynaptic transmembrane protein involved in synaptogenesis, has been predicted to be a promising candidate gene for autism and other neurological disorders [1518]
This is the first study from India on the role of the NLGN3 gene in autism

Summary

Introduction

Autism (MIM 209850) is a complex neurodevelopmental disorder that is characterised by impaired verbal and nonverbal communication and social interaction, accompanied by restricted and stereotyped behavior [1,2]. The aetiology of autism is largely unknown, but many studies have shown that genetic factors play a major. Hegde R et al Genetic analysis of NLGN3 gene in autism role, along with environmental factors. The genetic architecture of autism is complex. Autism shows diverse forms of genetic variation, differing in frequency (i.e., very rare, rare, and common variations), the pattern of inheritance (i.e., autosomal, X-linked, and de novo variations), the type of variation (i.e., structural—including aneuploidy, copy number variations, indel mutations, and single-nucleotide variations), and mode of action (additive, recessive, dominant, and hemizygous) [5,6]. The causes of autism may be heritable, de novo, or both. Some family and twin studies have shown that autism is highly heritable. The co-occurrence rate of autism in siblings is approximately 45 times greater than in the general population.

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