TY - JOUR T1 - A <em>de novo</em> paradigm for male infertility JF - bioRxiv DO - 10.1101/2021.02.27.433155 SP - 2021.02.27.433155 AU - MS Oud AU - RM Smits AU - HE Smith AU - FK Mastrorosa AU - GS Holt AU - BJ Houston AU - PF de Vries AU - BKS Alobaidi AU - LE Batty AU - H Ismail AU - J Greenwood AU - H Sheth AU - A Mikulasova AU - GDN Astuti AU - C Gilissen AU - K McEleny AU - H Turner AU - J Coxhead AU - S Cockell AU - DDM Braat AU - K Fleischer AU - KWM D’Hauwers AU - E Schaafsma AU - GEMINI Consortium AU - L Nagirnaja AU - DF Conrad AU - C Friedrich AU - S Kliesch AU - KI Aston AU - A Riera-Escamilla AU - C Krausz AU - C Gonzaga-Jauregui AU - M Santibanez-Koref AU - DJ Elliott AU - LELM Vissers AU - F Tüttelmann AU - MK O’Bryan AU - L Ramos AU - MJ Xavier AU - GW van der Heijden AU - JA Veltman Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/02/27/2021.02.27.433155.abstract N2 - Introduction De novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. 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 splicing2. 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.Competing Interest StatementThe authors have declared no competing interest. ER -