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.

Keywords: Klinefelter syndrome; Y-chromosomal microdeletion; andro-exome pipeline; assisted reproductive technology (ART); azoospermia; chronic disease; clinical guidelines; congenital absence of vas deference; congenital hypogonadotropic hypogonadism; diagnostic gene panel; disorders of sex development; exomes; genetic cause; genetic counselling; genetics; globozoospermia; male infertility; molecular diagnostics; multiple morphological abnormalities of the sperm flagella; oligogenic inheritance; pathogenic variant; pleiotropic genes; severe oligozoospermia; spermatogenic failure; testicular sperm extraction (TESE); translational research.

Fig. 1

Status quo in genetics of male infertility. (a) Aetiology of male infertility and proportion of genetically diagnosed and idiopathic cases in the subgroups of patients with reduced sperm counts (based on data from⁴). (b) Added value of genetic testing. (c) Established genetic causes of male factor infertility. CBAVD, congenital absence of vas deferens; het, heterozygous; hom, homozygous; (L)P, (likely) pathogenic; m, moderate; s, severe.

Fig. 2

Perspectives to uncover ‘hidden’ genetics of male infertility and the link to general health. (a) Variable penetrance and expressivity of rare pathogenic variants. (b) Alternative genetic factors contributing to male infertility; (c) shared genetic landscape of male infertility and general health. CHH, congenital hypogonadotropic hypogonadism; DSD, disorders of sex development; HH, hypogonadotropic hypogonadism; HPG, hypothalamic–pituitary-gonadal; KS, Klinefelter syndrome; LoF, loss-of-function; LP, likely pathogenic; NOA, non-obstructive azoospermia; P, pathogenic; SO, severe oligozoospermia.