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

This study looked at the genetics of autism in 42 Polish families by examining DNA from children with autism, their parents, and unaffected siblings. Researchers found that different types of autism may have different genetic causes - some involving new genetic changes, others involving inherited changes from both parents. The study identified genetic variants in genes important for brain function and development, confirming that autism has complex genetic causes that vary between individuals.

This family-based genetic study examined 42 Polish families (139 individuals) affected by autism spectrum disorder using targeted sequencing of 236 genes. Researchers analyzed rare inherited and de novo variants in probands, parents, and unaffected siblings. The study revealed distinct inheritance patterns across different autism presentations: de novo variants were more common in atypical autism, while biparental inheritance was more frequent in Asperger syndrome. Maternally inherited variants showed enrichment in regulatory regions.

Variants were identified in high-confidence autism risk genes affecting synaptic function and brain development pathways. Five variants of uncertain significance were detected across multiple genes, highlighting the genetic complexity and heterogeneity underlying autism spectrum disorders.

Findings support the genetic heterogeneity of autism and suggest that genetic testing approaches may need to consider different inheritance patterns for different autism presentations. The identification of variants in synaptic and neurogenesis genes reinforces these as important therapeutic targets, though clinical utility of identified variants requires further validation.

Study limited to Polish population which may not generalize to other ethnic groups. Sample size of 42 families is relatively small for genetic studies. Targeted sequencing panel may miss variants outside the 236 selected genes. Clinical significance of five variants remains uncertain.

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,,,, and, converging on pathways central to synaptic function and neurogenesis.

Across the cohort, five variants of uncertain significance (VUS) were identified, comprising two inherited variants inand additional variants in,, and. 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.