Familial Molecular Burden in Autism Spectrum Disorder: A Next-Generation Sequencing Study of Polish Affected Families

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition with a complex genetic architecture. Dissecting the interplay between inherited variants and high-impact de novo variants is critical for understanding its etiology. We conducted a family-based study involving 42 families with ASD (139 individuals). Using a targeted next-generation sequencing (NGS) panel of 236 genes, we identified and characterized rare inherited and de novo variants in affected probands, parents, and unaffected siblings. Our analysis revealed a complex genetic landscape marked by diverse inheritance patterns. De novo variants were predominantly observed in individuals with atypical autism, while biparental (homozygous) inheritance was more common in Asperger syndrome. Maternally inherited variants showed significant enrichment in intronic regions, pointing to a potential regulatory role. We also detected variants in several high-confidence ASD risk genes, including <i>SHANK3</i>, <i>MYT1L</i>, <i>MCPH1</i>, <i>NIPBL</i>, and <i>TSC2</i>, converging on pathways central to synaptic function and neurogenesis. Across the cohort, five variants of uncertain significance (VUS) were identified, comprising two inherited variants in <i>ABCC8</i> and additional variants in <i>CUL23</i>, <i>TSC2</i>, and <i>MCPH1</i>. Our findings underscore the profound genetic heterogeneity of ASD and suggest that distinct genetic mechanisms and inheritance patterns may contribute to different clinical presentations within the spectrum. This highlights the power of family-based genomic analyses in elucidating the complex interplay of inherited and de novo variants that underlies ASD.