Genetic insights into male autism spectrum disorder in a small cohort of Indian simplex families: findings from whole exome sequencing

Evidence also emphasises that ASD is programmed during the in utero period, with multiple prenatal and postnatal factors influencing the epigenome and contributing to the onset of ASD.1 Disruption in the neuronal network across various developmental stages leads to neurodevelopmental disorders,2 which are characterised by dysregulated neuronal communications leading to a vast array of clinical features.3 ASD predominantly impacts an individual’s communication, behaviour and social interaction skills. [...]variants were annotated using the variant effect predictor by applying parameters such as depth ≥20, genotype quality ≥20, variant allele frequency ≥0.5 and allelic depth at the mutated base >10. Subsequently, genes were prioritised based on two distinct criteria: (i) ‘reported’ genes in Simons Foundation Autism Research Initiative (SFARI) database, among these SFARI genes with an Evaluation of Autism Gene Link Evidence (EAGLE) score >7 were considered ‘high-risk’ genes associated with the ASD phenotype and (ii) ‘unreported’ genes were referred to as novel genes. Table 1 ‘High-risk’ genes associated with ASD phenotype carrying damaging variants Case ID Symbol Inherited/De novo MAF (Genome Asia) Consequences Variant type Phenotype associated (animal models) VABS score 030C CACNA1D Inherited 0.000289 c.1697A>G Missense variant Restricted, repetitive and perseverative behaviour Moderately low 105C RELN Inherited – c.5305G>A Missense variant Decreased social interaction Low 081C NRXN2 Inherited – c.3461G>A Missense variant Vocalisation pattern/social behaviour pattern Low 092C SHANK2 Inherited – c.400G>T Missense variant Vocalisation pattern/social behaviour pattern Moderately low 092C ZNF462 Inherited – c.5043C>G Missense variant Syndromic ASD form with ADHD Moderately low 090C WDFY3 De novo – c.7753–7754 CCA>C LoF Macrocephaly, deficit in motor coordination, associative learning Low 034C BRSK2 De novo – c.978G>C LoF Social impairment Moderately low 010C DEAF1 De novo – c.670C>T Missense variant Memory deficits and increased anxiety-like behaviour Low ADHD, Attention deficit hyperactivity disorder; ASD, autism spectrum disorder; ID, identification number; LOF, loss-of-function variants; MAF, minor allele frequency;