Faculty Collaboration Database

A de novo paradigm for male infertility. Nat Commun 2022 Jan 10;13(1):154

Date

01/12/2022

Pubmed ID

35013161

Pubmed Central ID

PMC8748898

DOI

10.1038/s41467-021-27132-8

Scopus ID

2-s2.0-85122860866 (requires institutional sign-in at Scopus site)   28 Citations

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 List

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, Genetics of Male Infertility Initiative (GEMINI) consortium, 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, Tüttelmann F, O'Bryan MK, Ramos L, Xavier MJ, van der Heijden GW, Veltman JA

Author

Jay I. Sandlow MD Chair, Professor in the Urologic Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Azoospermia
Case-Control Studies
Cell Cycle Proteins
DNA-Binding Proteins
Exome
Gene Expression
Gene Expression Profiling
Genetic Predisposition to Disease
Humans
Loss of Function Mutation
Male
Mutation, Missense
Oligospermia
RNA-Binding Proteins
Tumor Suppressor Proteins