In-silico phenotype-correlation analysis of Inherited variations in Autism Spectrum Disorder families identify complex interplay between genes encoding Sensory functions and Repetitive-Behaviours- a pilot study from India

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a strong genetic basis. Most genetic studies on ASD emphasize de novo mutations, while inherited rare variants remain understudied. We hypothesize that subtle, inherited ASD-related traits accumulate across generations and manifest as clinical ASD in offspring. To investigate this, we extracted inherited variations from our trio-based Whole Exome Sequences (WES) of 23 simplex ASD families (accession number PRJNA1071313 and PRJNA1072259). Data was processed in BWA, GATK and VarScan. Variants were annotated, filtered for functional impact, and scored using a novel ‘weighted scoring’ approach based on evolutionary intolerance. Overall 751 ‘weighted-genes’ with evolutionary and functional significance hosted pathogenic inherited variations. 149 genes (20%) carrying inherited-variations were enriched for core ASD-behaviours like social-interaction and restrictive repetitive behaviours (RRB) and 200 genes (26.6%) for associated behaviours like hyperactivity, communication, intelligence and mood. Overall 225 genes had neuronal-functions (p-value 3.799E-20), 116 inherited genes with sensory processing roles- particularly auditory and nociceptive- also shared RRB functions; 232 genes associated with seizures/epilepsy and 71.43% of genes associated to social interaction deficits also caused seizures. Brain tissue expression analysis revealed 95 and 195 prenatally and postnatally upregulated genes enriched with neurodevelopmental and neurotransmission functions, respectively; protein-protein-interactions were identified, suggesting genes BUB1, HMGA2, HDAC2, KALRN, SORL1, IGF2, FASN, WFS1 as promising new-candidates for ASD. In our ASD cohort, genes regulating sensory function and neuronal development were also RRB producing genes- supporting a multigenic, additive risk model of ASD- suggests a promising new avenue for diagnosis and intervention.