The genetic orchestra of autism and its intersections with epilepsy, intellectual disability, and ADHD.

Abstract

Autism is a complex condition with marked phenotypic variability and a multifactorial etiology orchestrated by diverse genetic and environmental influences. In this review, we dissect what we refer to as autism's "genetic orchestra", spanning from the high-impact "soloists", de novo and ultra-rare variants with large effect sizes, to the "polyphonic background" of common variants which individually exert modest effects but collectively have significant impact. We examine how this orchestra wires neural circuits, with convergent biological pathways modulating synaptic function and chromatin remodeling. Although de novo, rare, and common variants are often studied independently, converging evidence supports a model whereby their influences are largely additive. This genetic orchestra is not condition-specific; autism frequently co-occurs with other neurodevelopmental and psychiatric conditions, reflecting substantial pleiotropy across both rare and common variant landscapes. Notably, ultra-rare variants tend to associate with co-occurring intellectual disability, ADHD, epilepsy, and psychiatric conditions highlighting their high phenotypic impact. Beyond genetics, layers of environmental and contextual factors further modulate clinical outcomes. In this framework, we also discuss the challenges of identifying genetic variants associated with autism through clinical genetic testing, where yields remain context-dependent, varying by sex and co-occurring conditions. Finally, we address current limitations and future directions in refining our understanding of autism's genetic basis.