@article{a1026366556345e19cf126e6f5d202c1,
title = "A de novo paradigm for male infertility",
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.",
author = "{Genetics of Male Infertility Initiative (GEMINI) consortium} and Oud, {M. S.} and Smits, {R. M.} and Smith, {H. E.} and Mastrorosa, {F. K.} and Holt, {G. S.} and Houston, {B. J.} and {de Vries}, {P. F.} and Alobaidi, {B. K.S.} and Batty, {L. E.} and H. Ismail and J. Greenwood and H. Sheth and A. Mikulasova and Astuti, {G. D.N.} and C. Gilissen and K. McEleny and H. Turner and J. Coxhead and S. Cockell and Braat, {D. D.M.} and K. Fleischer and D{\textquoteright}Hauwers, {K. W.M.} and E. Schaafsma and Conrad, {Donald F.} and Liina Nagirnaja and Aston, {Kenneth I.} and Carrell, {Douglas T.} and Hotaling, {James M.} and Jenkins, {Timothy G.} and Rob McLachlan and O{\textquoteright}Bryan, {Moira K.} and Schlegel, {Peter N.} and Eisenberg, {Michael L.} and Sandlow, {Jay I.} and Jungheim, {Emily S.} and Omurtag, {Kenan R.} and Lopes, {Alexandra M.} and Susana Seixas and Filipa Carvalho and Susana Fernandes and Alberto Barros and Jo{\~a}o Gon{\c c}alves and Iris Caetano and Gra{\c c}a Pinto and S{\'o}nia Correia and Maris Laan and Margus Punab and Meyts, {Ewa Rajpert De} and Niels J{\o}rgensen and Kristian Almstrup and Krausz, {Csilla G.} and Jarvi, {Keith A.} and L. Nagirnaja and Conrad, {D. F.} and C. Friedrich and S. Kliesch and A. Riera-Escamilla and C. Gonzaga-Jauregui and M. Santibanez-Koref and Elliott, {D. J.} and Vissers, {L. E.L.M.} and F. T{\"u}ttelmann and L. Ramos and Xavier, {M. J.} and {van der Heijden}, {G. W.} and Veltman, {J. A.}",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
day = "1",
doi = "10.1038/s41467-021-27132-8",
language = "English",
volume = "13",
journal = "Nature communications",
issn = "2041-1723",
number = "1",
}