Translational aspects of novel findings in genetics of male infertility—status quo 2021

Abstract

Introduction Male factor infertility concerns 7–10% of men and among these 40–60% remain unexplained. Sources of data This review is based on recent published literature regarding the genetic causes of male infertility. Areas of agreement Screening for karyotype abnormalities, biallelic pathogenic variants in the CFTR gene and Y-chromosomal microdeletions have been routine in andrology practice for >20 years, explaining ~10% of infertility cases. Rare specific conditions, such as congenital hypogonadotropic hypogonadism, disorders of sex development and defects of sperm morphology and motility, are caused by pathogenic variants in recurrently affected genes, which facilitate high diagnostic yield (40–60%) of targeted gene panel-based testing. Areas of controversy Progress in mapping monogenic causes of quantitative spermatogenic failure, the major form of male infertility, has been slower. No ‘recurrently’ mutated key gene has been identified and worldwide, a few hundred patients in total have been assigned a possible monogenic cause. Growing points Given the high genetic heterogeneity, an optimal approach to screen for heterogenous genetic causes of spermatogenic failure is sequencing exomes or in perspective, genomes. Clinical guidelines developed by multidisciplinary experts are needed for smooth integration of expanded molecular diagnostics in the routine management of infertile men. Areas timely for developing research Di−/oligogenic causes, structural and common variants implicated in multifactorial inheritance may explain the ‘hidden’ genetic factors. It is also critical to understand how the recently identified diverse genetic factors of infertility link to general male health concerns across lifespan and how the clinical assessment could benefit from this knowledge.

Genome and Epigenome Disorders and Male Infertility: Feedback from 15 Years of Clinical and Research Experience

“…Genetic causes of male infertility are found in up to 10% of cases, mainly in cases of severe quantitative infertility defects, whereas 40–60% of cases with spermatogenic impairment remain unexplained and, among moderate oligozoospermia cases, this fraction is close to 80% [ 2 ]. The extreme clinical and genetic heterogeneity of male infertility and the reduced reproductive fitness of affected males are two major challenges for the identification of new causative genetic factors.…”

“…Advances in next generation sequencing technologies have been a significant asset in the identification of novel genes responsible for a large panel of human pathologies. Similarly, the application of next generation sequencing to male infertility allowed for the identification of several new genetic factors [ 2 ]. The last published standardized clinical validity assessment of monogenic causes of male infertility reported 120 genes that are linked to 104 infertility phenotypes [ 8 ].…”

Microdeletions and microduplications linked to severe congenital disorders in infertile men

“…CNVs may modulate the process of spermatogenesis through altered gene dosage effect, impaired homologous recombination, and/or genomic instability leading to errors in chromosomal segregation. So far, data on the role and clinical validity of CNVs predisposing to male infertility is limited 3 . The only CNVs included in the diagnostic workup of men with spermatogenic failure (SPGF) are sporadic microdeletions encompassing three Azoospermia Factor regions ( AZFa, AZFb or AZFc ) located in the Y chromosome and mostly leading to complete lack of mature sperm 2 .…”

A loss-of-function variant in SSFA2 causes male infertility with globozoospermia and failed oocyte activation

“…Infertility, defined by the World Health Organization (WHO) as the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse, is a major concern in public health and affects approximately 8-12% of couples worldwide [ 1 , 2 ]. Approximately 20-70% of affected couples are affected by male factors, and among these male factors, 40–60% remain unexplained owing to a multifactorial pathological condition [ 3 , 4 ]. Genetic factors account for at least 15% of male infertility cases [ 5 ].…”