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

Early paternal germline mosaicism and age-related accumulation of de novo mutations, shaped by spermatogonial selection

De novo mutations in the paternal germline are a major cause of developmental disorders, but the respective contributions of mutation timing, paternal age and spermatogonial selection within an individual father remained unclear. The authors combined trio whole-genome sequencing from 167 families with deep targeted NanoSeq profiling of sperm from 127 fathers of children with confirmed pathogenic de novo mutations. Transmitted mutational burden, and paternal sperm mutation burden, spectra and selection landscape, were indistinguishable from population reference cohorts. Six fathers carried pathogenic early mosaic variants detectable in sperm at variant allele fractions of 0.7% to 14.8%, creating individual recurrence-risk outliers. At cohort level, however, early mosaics accounted for only about 8% of the aggregated pathogenic exome-wide burden, versus about 18% from known positively selected drivers and about 74% from other rare variants accumulating with paternal age.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This paper finally puts numbers on a conversation we have every week in clinic: recurrence risk after a de novo mutation. Six fathers out of 127 with pathogenic sperm mosaicism is enough to justify offering sperm testing when further pregnancies are planned, while stressing that most of the risk still stems from ordinary age-related mutation accumulation. The weakness is sample size: six events are not enough to set a variant allele fraction threshold above which counselling changes.

Analysis by Dr Thibaut Benquey