A de novo paradigm for male infertility
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Published:2022-01-10
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Oud M. S.ORCID, Smits R. M., Smith H. E., Mastrorosa F. K.ORCID, Holt G. S., Houston B. J., de Vries P. F., Alobaidi B. K. S.ORCID, Batty L. E., Ismail H., Greenwood J., Sheth H.ORCID, Mikulasova A., Astuti G. D. N., Gilissen C.ORCID, McEleny K., Turner H., Coxhead J.ORCID, Cockell S., Braat D. D. M.ORCID, 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.ORCID, Conrad D. F.ORCID, Friedrich C., Kliesch S.ORCID, Aston K. I., Riera-Escamilla A., Krausz C., Gonzaga-Jauregui C., Santibanez-Koref M., Elliott D. J., Vissers L. E. L. M.ORCID, Tüttelmann F.ORCID, O’Bryan M. K.ORCID, Ramos L.ORCID, Xavier M. J.ORCID, van der Heijden G. W.ORCID, Veltman J. A.ORCID,
Abstract
AbstractDe 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.
Funder
Wellcome Trust Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference69 articles.
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