A de novo paradigm for male infertility

Abstract

De novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

WWC2 expression in the testis: Implications for spermatogenesis and male fertility

“…As a further control group, exome sequencing data of 5784 Dutch proven fathers were screened. These men were part of trio‐exome sequencing because of the child's suspected genetics disease and were screened at the Radboudumc genome diagnostics center in Nijmegen, The Netherlands, as part of routine diagnostic genetic testing 24 . The data were used under the section 7:467 of the Dutch Civil Code that allows for anonymous usage of patient material data for medical statistics or other medical/scientific research.…”

“…Patients with identified genetic cause for male infertility (e.g., variants in M1AP or TEX11 ) 22 were excluded from the analysis. For further variant selection, those variants found in control men with intact spermatogenesis ( n = 104), an external cohort of proven fathers ( n = 5784) 24,32 and those found in men not exhibiting the expected phenotype of reduced sperm count (e.g., men with teratozoospermia) as well as variants found in a patient's father were excluded. Based on the observed/expected (o/e) score for loss‐of‐function (LoF) variants of 0.39, we considered an autosomal dominant mode of inheritance as possible.…”

The ‘-ics’ of male reproduction: genomics, epigenetics, proteomics, metabolomics, and microbiomics

“…Lastly, another study evaluated 185 men with idiopathic NOA along with their parents (trios of proband and parents) to identify de novo mutations (DNM) that could be responsible for their spermatogenic failure [19 ▪ ]. Genomic DNA was isolated from each trio and WES was performed.…”

“…Genomic DNA was isolated from each trio and WES was performed. The authors identified 192 rare DNMs, including 145 that cause alteration in protein characteristics [19 ▪ ]. Additionally, two rare de novo copy number variations also were identified [19 ▪ ].…”

Testis‐specific serine kinase 3 is required for sperm morphogenesis and male fertility

“…Oligoteratozoospermia, a cause of idiopathic infertility in men, is a failure of spermatogenesis leading to both a decrease in sperm counts (oligozoospermia) and the presence of abnormal sperm forms (teratozoospermia) 1 . Genetic factors are considered to be one of the causes of nonobstructive oligozoospermia 2 . Multiple genes responsible for azoospermia have been reported to date, 3 and the utilization of this information for the development of infertility diagnosis, 4,5 or the development of novel contraceptives targeting crucial reproductive tract‐specific proteins, 6,7 holds promise.…”