Diverse monogenic subforms of human spermatogenic failure

Abstract

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human “knockouts”, and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.

DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia

“…To elucidate the impact of monogenic variants in the genes located within the Y-chromosomal AZFa region, we screened whole exome sequencing (WES) data of 1,655 well-characterized men from the Male Reproductive Genomics (MERGE) study with unexplained crypto-or azoospermia for high-impact variants in USP9Y, DDX3Y, and UTY and identified three unrelated men of European ancestry carrying different LoF variants in DDX3Y. In addition, a further LoF variant in DDX3Y was identified in WES data of the Genetics of Male Infertility Initiative (GEMINI) study 25 . All four variants are absent in the gnomAD database (v2.1.1), abrogate at least the sequence of the C-terminal helicase domain (Fig.…”

In vivoversusin silicoassessment of potentially pathogenic missense variants in human reproductive genes

“…One mutation in M1AP (ENST00000536235.1: c.G949A:p.Gly317Arg) was selected from a list of variants thought to be causative for NOA identified in a cohort of 924 unrelated cases exome-sequenced by the GEMINI Consortium (82). This list of genotypes was generated by a computational pipeline intended to identify rare monogenic causes of NOA (82). This mutation was found as a heterozygote in a single sporadic case with maturation arrest testis histology and no family history of consanguinity.…”

“…Three variants identified in male infertility patients were nominated for mouse modeling. One mutation in M1AP (ENST00000536235.1: c.G949A:p.Gly317Arg) was selected from a list of variants thought to be causative for NOA identified in a cohort of 924 unrelated cases exome-sequenced by the GEMINI Consortium (82). This list of genotypes was generated by a computational pipeline intended to identify rare monogenic causes of NOA (82).…”

Small RNAs in andrology: Small messengers with large perspectives

“…However, germ cells actually have their own specific subtype of sncRNA. The piRNAs appear nearly unique to germ cells and are essential for spermatogenesis as recently shown by an increasing number of studies reporting defects in the piRNA‐related proteins among men with meiotic arrest and non‐obstructive azoospermia 21–29 . In spermatogenesis, the piRNAs are engaged both in the regulation of mRNA degradation 30 and translational activation of other mRNAs that are specifically needed in spermatids, during spermiogenesis 31 .…”

“…The piRNAs appear nearly unique to germ cells and are essential for spermatogenesis as recently shown by an increasing number of studies reporting defects in the piRNArelated proteins among men with meiotic arrest and non-obstructive azoospermia. [21][22][23][24][25][26][27][28][29] In spermatogenesis, the piRNAs are engaged both in the regulation of mRNA degradation 30 and translational activation of other mRNAs that are specifically needed in spermatids, during spermiogenesis. 31 However, it is also well-described that piR-NAs engage in the repression of transposable elements in fetal germ cells, where DNA methylation is completely erased.…”