Identification of Novel Gene variants for Autism Spectrum Disorder in an Indian Patient using Whole Exome Sequencing

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction, along with restricted and repetitive behaviour patterns, interests or activities. Its prevalence has risen over the past few years, being four times more common in boys than girls. The cause of ASD is unclear, its etiology involves genetic, environmental, and gene-environment interactions. While past studies highlighted clinical genetic risks, genetic complexity of ASD, with variants of diverse frequencies, type, and inheritance patterns, requires further exploration for better management of disease. Researches have shown that the whole exome sequencing can be used to identify genetic variants associated with genetically heterogeneous conditions. The purpose of this study is to identify genetic variants by employing whole exome sequencing in an Indian ASD patient. Methods: A female patient of age within 0-5 years, having characteristic features like hyperactivity and language impairment, was investigated and diagnosed using DSM-5 criteria. Peripheral blood sample collection was done followed by DNA extraction and whole exome sequencing. Variants analysis, identification and annotation were done using bioinformatics tools and databases. Identified pathogenic variants were reconfirmed by Sanger sequencing. Results and conclusion: Our study uncover four genetic variations, comprising three missense variations in KIF1A (c.3839C>T), SETD5 (c.314A>C), MAPK81P3 (c.2849C>T), and one-stop gain variation in ERMARD (c.1523G>A). The ERMARD stop gain variation, predicted to induce nonsense-mediated decay, alter normal protein function through truncation and classified as likely pathogenic based on the ACMG guidelines and current available scientific evidence. In conclusion, we identified a likely pathogenic variant in ERMARD along with three missense variants in KIF1A, SETD5 and MAPK81P3 respectively. These findings suggest the potential contribution of ERMARD mutations to ASD susceptibility, emphasizing the need for further validation through functional studies. Keywords: Autism spectrum disorder, neurodevelopmental disorder, whole exome sequencing, language impairment, bioinformatics, missense variation