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<p>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 (<i>p</i> = 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 <i>BUB1</i>,<i> HMGA2</i>,<i> HDAC2</i>,<i> KALRN</i>,<i> SORL1</i>,<i> IGF2</i>,<i> FASN</i>,<i> WFS1</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Meghana Kommerahalli RameshRaju,
  • Snijesh Valiya Parambath,
  • Durbagula Srividhya,
  • Bhagyalakshmi Shankarappa,
  • Ramachandra Nallur Basappa,
  • Ashitha S.Niranjana Murthy

摘要

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.