Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men

Abstract

Purpose: Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA. Methods: Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts). Results: We found strong evidence for 5 novel genes likely responsible for MA ( ADAD2 , TERB1 , SHOC1 , MSH4 , and RAD21L1 ), for which mouse knockout (KO) models are concordant with the human phenotype. Four of them were validated in the two independent MA cohorts. In addition, 9 patients carried pathogenic variants in 7 previously reported genes - TEX14 , DMRT1 , TEX11 , SYCE1 , MEIOB , MEI1 and STAG3 - allowing to upgrade the clinical significance of these genes for diagnostic purposes. Our meiotic studies provide novel insight into the functional consequences of the variants, supporting their pathogenic role. Conclusions: Our findings contribute substantially to the development of a pre-TESE prognostic gene panel. If properly validated, the genetic diagnosis of complete MA prior to surgical interventions is clinically relevant. Wider implications include the understanding of potential genetic links between NOA and cancer predisposition, and between NOA and premature ovarian failure.

TRIM71deficiency causes germ cell loss during mouse embryogenesis and promotes human male infertility

“…Lately, several genes have been identified as monogenic causes for azoospermia due to meiotic arrest (e.g. TEX11 62 , STAG3 63 , M1AP 64 and SHOC1 65 ). However, the SCO phenotype seems to be a highly heterogeneous condition, as indicated by our data, making the identification of monogenic causes specially challenging.…”

Genetics of Azoospermia

“…MEI1 : is implicated in DBS formation, and, along with other NOA causing genes such as MEIOB, TEX11, TEX15 and SYCE1 , contributes to the formation and maintenance of the synaptonemal complex and crossovers between homologous chromosomes [ 11 ]. Recessive mutations in MEI1 have been reported in NOA patients exhibiting complete SCA [ 10 , 88 , 89 ].…”

“…MEIOB : besides crossover formation and promotion of synapsis during meiosis, it is especially required for DBS repair [ 132 , 133 ]. Men carrying biallelic LoF mutations in this gene also present complete SCA [ 10 , 90 , 91 ], resulting in an arrest at metaphase I [ 10 ]. Interestingly enough, MEIOB LoF variants cluster in exon 12, suggesting a hotspot variant region, at least in the Arab/Pakistani population [ 10 , 91 , 134 ].…”

Editorial for the special issue on the molecular genetics of male infertility

“…A number of NOA genes, specifically those causing meiotic arrest, have been discovered and immediately validated thanks to data sharing between different laboratories and the members of the International Male Infertility Genomics Consortium (http://www.imigc .org) and the Genetics of Male Infertility Initiative (GEMINI) consortium ( http:// www.gemin i.conra dlab.org) (Kasak and Laan 2021;Xavier et al 2021;Krausz et al 2020;Capalbo et al 2020). In this issue, we can read about mutations in three genes (TERB1, TERB2 and NAJMIN) that play a role in the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for completion of meiosis (Salas-Huetos et al 2021).…”

“…Salas-Huetos and collaborators report recessive mutations in these genes and propose defects in TERB2 and NAJMIN as novel causes of meiotic arrest in human. Since two other very recent articles reported TERB1 mutations in patients with meiotic arrest (Krausz et al 2020;Alhathal et al 2020), the Salas-Huetos et al study 2021contributes to the clinical upgrading of the gene-disease relationship between TERB1 mutations and spermatocytic arrest.…”