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.
Highlights
De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness
A systematic analysis of the role of de novo mutations (DNMs) in male infertility had not been attempted, even though a pilot exome sequencing study in 13 infertile men and their parents was recently published[7]. This is partly explained by a lack of basic research in male reproductive health in general[4,8], and by the practical challenges of collecting parental samples for this disorder, which is typically diagnosed in adults. We address this lack of knowledge by analysing exome sequencing data of 185 infertile males and their parents and reporting on our findings of 29 DNM in these men which are likely causative for the infertility phenotype, based on variant and gene level evidence
We identify a number of promising candidate genes for male infertility, including the mRNA splicing gene RBM5, which contains a possibly causative DNM in our trio cohort, and possibly causative heterozygous variants in six additional patients for which parental information is not available
Summary
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. A systematic analysis of the role of DNMs in male infertility had not been attempted, even though a pilot exome sequencing study in 13 infertile men and their parents was recently published[7] This is partly explained by a lack of basic research in male reproductive health in general[4,8], and by the practical challenges of collecting parental samples for this disorder, which is typically diagnosed in adults. This work suggests a potential role for DNM as a cause of severe male infertility and addresses the need for further investigation in larger patient–parent trio cohorts to solidify these results
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