Introduction De novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness 1 . We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing 2 . In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

A de novo paradigm for male infertility