In silico Genotype-Phenotype Correlation Analysis of Inherited Variations in Autism Spectrum Disorder Families Identify an Interplay between Sensory Function and Repetitive-behaviour Genes.

This study looked at genetic information from 23 families with autism to understand how autism traits might be passed down through generations. Researchers found that many genes involved in autism also affect sensory processing and repetitive behaviors. The study suggests that autism may result from small genetic changes from both parents combining together, rather than just new genetic changes. This could help explain why autism sometimes runs in families even when parents don't have obvious autism traits themselves.

This computational study analyzed inherited genetic variations in 23 families with autism spectrum disorder (ASD) using whole exome sequencing. Researchers identified 751 genes with evolutionary and neuronal functions that host deleterious inherited variations. Key findings showed 149 genes (20%) were enriched for core ASD behaviors like social interaction difficulties and repetitive behaviors, while 200 genes (26.6%) were associated with related behaviors including hyperactivity and communication issues. Notably, 62% of repetitive behavior genes also displayed sensory functions, and 71% of social interaction deficit genes were linked to seizures.

The study suggests inherited genetic variations accumulate across generations, supporting a multigenic model where subtle traits from unrelated parents combine to manifest clinically as ASD in offspring.

Findings suggest genetic counseling should consider inherited variations from both parents, not just de novo mutations. The sensory-repetitive behavior gene overlap supports integrated therapeutic approaches addressing both domains. The seizure-social interaction gene connection highlights importance of seizure screening in socially affected individuals with autism.

Small sample size of only 23 families limits generalizability. Computational analysis without experimental validation. No comparison to control families without autism. Functional predictions may not translate to actual biological effects. Future year (2026) suggests this may be preliminary or projected data.

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 clinically manifest as ASD in offspring. To investigate this, we extracted inherited variations from 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 'weighted scoring' approach based on intolerance to genetic alterations. Overall 751 'weighted-genes' with evolutionary and neuronal functions hosting deleterious inherited variations were functionally annotated for ASD-linked behaviours and comorbidities. We found 149 (20%) genes enriched for core ASD-behaviours like social-interaction and restrictive repetitive behaviours (RRB), 200 genes (26.6%) for associated-behaviours like hyperactivity, communication, intelligence and mood and 225 genes displayed neuronal-functions (p = 3.799E-20).

Importantly, 62% of RRB genes displayed sensory functions and 71.43% of genes associated to social interaction deficits were also linked to seizures. Brain tissue expression analysis of all 751 genes revealed 95 prenatally and 195 postnatally upregulated genes were enriched with neurodevelopmental and neurotransmission functions, respectively; protein-protein-interactions suggested genes BUB1, HMGA2, HDAC2, KALRN, SORL1, IGF2, FASN, WFS1 as promising new-candidates for ASD. In our ASD cohort, inherited variations in genes regulating sensory function and neurodevelopment were also RRB producing genes- supporting a multigenic, subdued but additive genetic load being passed down from unrelated parents to their offsprings- promising an underexplored avenue for autism genetic research.