A de novo paradigm for male infertility.

Oud, Manon S; Smits, Roos M; Smith, Hannah E; Mastrorosa, Francesco K; Holt, Giles S; Houston, Brendan J; de Vries, Petra F; Alobaidi, Bilal K S; Batty, Lois E; Ismail, H; Greenwood, J; Sheth, Harsh; Mikulasova, Aneta; Astuti, Galuh D N; Gilissen, Christian; McEleny, Kevin; Turner, H; Coxhead, Jonathan; Cockell, Simon; Braat, Didi D M; Fleischer, Kathrin; D'Hauwers, Kathleen W M; Schaafsma, Ewout; Genetics of Male Infertility Initiative (GEMINI) consortium; Nagirnaja, Liina; Conrad, Donald F; Friedrich, Corinna; Kliesch, Sabine; Aston, Kenneth I; Riera-Escamilla, Antoni; Krausz, Csilla; Gonzaga-Jauregui, Claudia; Santibanez-Koref, Mauro; Elliott, David J; Vissers, Lisenka E L M; Tüttelmann, Frank; O'Bryan, Moira K; Ramos, Liliana; Xavier, Miguel J; van der Heijden, Godfried W; Veltman, Joris A

Abstract

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10-5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10-4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.