A de novo paradigm for male infertility
Oud, Manon S (Radboudumc)
Smits, R. M. (Radboudumc)
Smith, H. E. (Newcastle University)
Mastrorosa, Francesco Kumara (Newcastle University)
Holt, G. S. (Newcastle University)
Houston, B. J. (The University of Melbourne)
de Vries, P. F. (Radboudumc)
Alobaidi, Bilal K. (Newcastle University)
Batty, L. E. (Newcastle University)
Ismail, H. (Newcastle University)
Greenwood, J. (The Newcastle upon Tyne Hospitals NHS Foundation Trust)
Sheth, Harsh (Institute of Human Genetics, Ahmedabad)
Mikulasova, A. (Newcastle University. Biosciences Institute, Faculty of Medical Sciences)
Astuti, G. D. N. (Diponegoro University. Division of Human Genetics, Center for Biomedical Research, Faculty of Medicine)
Gilissen, Christian (Radboudumc)
McEleny, K. (The Newcastle upon Tyne Hospitals NHS Foundation Trust)
Turner, H. (The Newcastle upon Tyne Hospitals NHS Foundation Trust)
Coxhead, Jonathan (Newcastle University)
Cockell, S. (Newcastle University, Newcastle upon Tyne)
Braat, Didi (Radboudumc)
Fleischer, K. (Radboudumc)
D'Hauwers, K. W. M. (Radboudumc)
Schaafsma, E. (Radboudumc)
Nagirnaja, Liina (Oregon Health & Science University)
Conrad, Donald F. (Oregon Health & Science University)
Friedrich, C. (University of Münster)
Kliesch, Sabine (University Hospital of Münster (Alemanya))
Aston, Kenneth I (University of Utah School of Medicine)
Riera-Escamilla, Antoni (Institut d'Investigació Biomèdica Sant Pau)
Krausz, Csilla (University of Florence)
Gonzaga-Jauregui, Claudia (Regeneron Genetics Center)
Santibanez-Koref, M. (Newcastle University)
Elliott, D. J. (Newcastle University)
Vissers, Lisenka (Radboudumc)
Tüttelmann, Frank (University of Münster)
O'Bryan, Moira Kathleen (The University of Melbourne)
Ramos, Liliana (Radboudumc)
Xavier, Miguel (Newcastle University)
van der Heijden, G. W. (Radboudumc)
Veltman, Joris A. (Newcastle University)
Universitat Autònoma de Barcelona

Fecha:	2022
Resumen:	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. Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Infertility ; Disease genetics ; DNA sequencing
Publicado en:	Nature communications, Vol. 13 (january 2022) , ISSN 2041-1723

DOI: 10.1038/s41467-021-27132-8
PMID: 35013161

10 p, 1.6 MB

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