Autism risk in offspring can be assessed through quantification of male sperm mosaicism

De novo mutations (DNMs) arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders (ASD) is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep whole genome sequencing, both for variants present in an offspring and evident only in father’s sperm, and identified single nucleotide, structural, and short tandem repeat variants. We found that mosaicism quantification can stratify ASD recurrence risk due to DNMs into the vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. Thus, this suggests that genetic counseling would benefit from the addition of sperm mosaicism assessment.