Mutation timing, accumulation, and selection in the male germline shape inheritance risk for developmental disorders.

Paternal age-related mutations and selection primarily shape de novo mutation risk for developmental disorders, with early mosaicism contributing to a smaller, high-risk subset.

• Why it matters: Understanding how mutation timing, paternal age, and spermatogonial selection influence transmissible risk is crucial for assessing developmental disorder inheritance and recurrence risks.
• What they did: The study analyzed 167 families using trio whole-genome sequencing and deep NanoSeq profiling of sperm from 127 fathers, identifying mutation patterns, spectra, and mosaic variants.
• The result: Findings show that most paternal de novo mutation risk is driven by age-related mutation accumulation and selection, while early mosaicism accounts for about 8% of pathogenic burden, highlighting rare but significant high-risk cases.