Author(s):
Oud, M.S. ; Smits, R.M. ; Smith, H.E. ; Mastrorosa, F.K. ; Holt, G.S. ; Houston, B.J. ; de Vries, P.F. ; Alobaidi, B.K.S. ; Batty, L.E. ; Ismail, H. ; Greenwood, J. ; Sheth, H. ; Mikulasova, A. ; Astuti, G.D.N. ; Gilissen, C. ; McEleny, K. ; Turner, H. ; Coxhead, J. ; Cockell, S. ; Braat, D.D.M. ; Fleischer, K. ; D’Hauwers, K.W.M. ; Schaafsma, E. ; Conrad, Donald F. ; Nagirnaja, Liina ; Aston, Kenneth I. ; Carrell, Douglas T. ; Hotaling, James M. ; Jenkins, Timothy G. ; McLachlan, Rob ; O’Bryan, Moira K. ; Schlegel, Peter N. ; Eisenberg, Michael L. ; Sandlow, Jay I. ; Jungheim, Emily S. ; Omurtag, Kenan R. ; Lopes, Alexandra M. ; Seixas, Susana ; Carvalho, Filipa ; Fernandes, Susana ; Barros, Alberto ; Gonçalves, João ; Caetano, Iris ; Pinto, Graça ; Correia, Sónia ; Laan, Maris ; Punab, Margus ; Meyts, Ewa Rajpert-De ; Jørgensen, Niels ; Almstrup, Kristian ; Krausz, Csilla G. ; Jarvi, Keith A. ; Nagirnaja, L. ; Conrad, D.F. ; Friedrich, C. ; Kliesch, S. ; Aston, K.I. ; Riera-Escamilla, A. ; Krausz, C. ; Gonzaga-Jauregui, C. ; Santibanez-Koref, M. ; Elliott, D. J. ; Vissers, L.E.L.M. ; Tüttelmann, F. ; O’Bryan, M.K. ; Ramos, L. ; Xavier, M.J. ; van der Heijden, G.W. ; Veltman, J.A.
Date: 2022
Persistent ID: http://hdl.handle.net/10400.18/8497
Origin: Repositório Científico do Instituto Nacional de Saúde
Subject(s): Male Infertility; Infertile Man; Spermatogenesis; Genética Humana; Doenças Genéticas
Description
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.
