A de novo paradigm for male infertility
Manon S. Oud, RM Smits, H E Smith, Francesco Mastrorosa, Giles Holt, Brendan J. Houston, Petra F. de Vries, B. Alobaidi, Lois E. Batty, Hoda Ismail, Joel Greenwood, Harsh Sheth, Aneta Mikulášová, Galuh Astuti, Christian Gilissen, Kevin McEleny, H Turner, Jonathan Coxhead, Simon Cockell, D.D.M. Braat, Kathrin Fleischer, K. W. M. D’Hauwers, Ewout Schaafsma, Donald F. Conrad, Liina Nagirnaja, Kenneth I. Aston, Douglas T. Carrell, James M. Hotaling, Timothy Jenkins, Rob McLachlan, Moira K. O’Bryan, Peter N. Schlegel, Michael L. Eisenberg, Jay Sandlow, Emily S. Jungheim, Kenan Omurtag, Alexandra M. Lopes, Susana Seixas, Filipa Carvalho, Susana Fernandes, Alberto Barros, João Gonçalves, Iris Caetano, Graça Pinto, Sónia Vladimira Correia, Maris Laan, Margus Punab, Ewa Rajpert‐De Meyts, Niels Jørgensen, Kristian Almstrup, Csilla Krausz, Keith Jarvi, Liina Nagirnaja, Donald F. Conrad, Corinna Friedrich, Sabine Kliesch, Kenneth I. Aston, Antoni Riera‐Escamilla, Csilla Krausz, Claudia Gonzaga‐Jauregui, Mauro Santibanez‐Koref, David J. Elliott, Lisenka E.L.M. Vissers, Frank Tüttelmann, Moira K. O’Bryan, Liliana Ramos, Miguel J. Xavier, Godfried W. van der Heijden, Joris A. Veltman
Abstract
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.