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A de novo paradigm for male infertility

Lookup NU author(s): Hannah Smith, Francesco Kumara Mastrorosa, Dr Giles Holt, Dr Brendan Houston, Dr Bilal AlobaidiORCiD, Lois Batty, Jackie Greenwood, Dr Harsh Sheth, Dr Aneta Mikulasova, Kevin McEleny, Dr Jonathan Coxhead, Dr Simon CockellORCiD, Dr Mauro Santibanez Koref, Professor David Elliott, Dr Miguel Garcia Dos Santos XavierORCiD, Professor Joris VeltmanORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 utilise 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 observe a significant enrichment of Loss-of-Function de novo mutations in Loss-of-Function-intolerant genes (p-value=1.00x10-5) 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=5.01x10-4) 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.

Publication metadata

Author(s): Oud MS, Smits RM, Smith HE, Mastrorosa FK, Holt GS, Houston BJ, de Vries PF, Alobaidi BKS, Batty LE, Ismail H, Greenwood J, Sheth H, Mikulasova A, Astuti GDN, Gilissen C, McEleny K, Turner H, Coxhead J, Cockell S, Braat DDM, Fleischer K, D'Hauwers KWM, Schaafsma E, Consortium GEMINI, Nagirnaja L, Conrad DF, Friedrich C, Kliesch S, Aston KI, Riera-Escamilla A, Krausz C, Gonzaga-Jauregui C, Santibanez-Koref M, Elliott DJ, Vissers LELM, Tuttelmann F, O'Bryan MK, Ramos L, Xavier MJ, van der Heijden GW, Veltman JA

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2022

Volume: 13

Issue: 154

Online publication date: 10/01/2022

Acceptance date: 02/11/2021

Date deposited: 11/01/2022

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/s41467-021-27132-8


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Funder referenceFunder name
BB/S008039/1Biotechnology and Biological Sciences Research Council (BBSRC)