Advanced Paternal Age Increases Autism Risk in Grandchildren via Female Lineage

Clinicians have long recognized that advanced paternal age is a robust risk factor for autism spectrum disorder in immediate offspring [1, 2]. This association is largely attributed to the accumulation of de novo mutations (spontaneous genetic alterations occurring for the first time in a family member) and epigenetic modifications in the male germline as men age [3, 4]. While these genetic variants contribute to the overall risk burden of neurodevelopmental conditions, the extent to which they persist or manifest across multiple generations remains poorly understood [5]. Current evidence suggests that while the individual risk from these mutations may be modest, their cumulative impact on population health is significant given the global trend toward delayed parenthood [2, 3]. A recent multigenerational analysis of national registry data examines whether these paternal age effects extend to the third generation, potentially clarifying the complex inheritance patterns observed in clinical practice.