The rising role of genetics in andrology research and clinical practice

Abstract

The term “androgenetics” refers to research focusing on genetics of male-specific conditions.¹ For the first time, Andrology publishes a Special Issue “Genetics in Andrology” solely devoted to androgenetics—a forward-looking milestone in the field. So far, andrology has lagged behind other medical fields in taking advantage of rapid technological (r)evolution and recent breakthroughs in genetics and genomics. In this Special Issue, 10 review articles and 15 original studies authored by researchers from around the world provide a comprehensive overview of the state-of-the-art, current, and perspective clinical applications of genetics in andrology. To facilitate a broad readership, an introductory article by Akbari et al.¹ is included covering the progress of androgenetics over 60 years and providing a glossary of the core terminology in medical genetics.

Since the discovery that the Klinefelter syndrome phenotype is linked to 47, XXY karyotype, cytogenetic analysis has been successfully introduced to the male infertility workup, explaining 3%–4% of cases² and adding value in clinical practice for patient counseling and management (e.g. original study by Zohdy et al. in this issue³). Access to whole-exome sequencing (WES) during the past 5–10 years has revealed the diverse landscape of monogenic infertility with over 600 proposed candidate genes.⁴ A thorough review by Riera-Escamilla and Nagirnaja⁵ including 19 WES-based studies in cohorts of unrelated cases with primary spermatogenic defects demonstrates the variability in detection rates of disease-causing variants across subphenotypes and different research settings. Across the studies, clinically relevant monogenic findings already explain 10%–20% cases of azoo/oligozoospermia and more than half of cases with 46, XY differences/disorders of sex development (DSD) or qualitative sperm defects.^5-8 It is likely that the forthcoming years will bring along a further increase in the diagnostic yield of genetic infertility due to rapidly dropping costs of whole-genome sequencing (WGS). The richer information content of WGS compared with WES allows for reliable detection of genomic structural variants, as demonstrated in the original study by Khan et al.⁹ analyzing family cases from Pakistan.

Due to high genetic and phenotypic heterogeneity, confirmation of novel gene–disease links has been a challenge. A large fraction of proposed gene–disease relationships has been reported in singleton cases or among the members of consanguineous families. To establish solid genotype-phenotype links, each finding must be confirmed in independent case(s), and their relevance to the routine clinical practice needs critical assessment. Stallmeyer et al.⁶ have undertaken an important task to evaluate the clinical validity of 313 candidate genes for diverse male infertility subtypes. In applying the standardized international evaluation criteria, only 70 genes with at least moderate evidence to contribute to the condition were reported. This is one step closer to routine utility of WES-based, advanced genetic testing offered by andrology clinics and infertility centers worldwide. An original study by Oud et al.¹⁰ represents another crucial contribution toward this goal, showing WES as a reliable first-tier method to simultaneously detect most common currently known genetic causes of male infertility—diverse monogenic conditions (including CFTR mutations), chromosomal abnormalities and AZF microdeletions. The diagnostic yield of this extended WES analysis already reached 23% in the clinical setting.

The clinical validity of tested genes and standardized assessment of variant pathogenicity is not only important for molecular diagnostics, but also for patient management decisions. A comprehensive review by Idris et al.⁷ covers 46, XY DSD cases published from 2018 to 2023, highlighting broad the phenotypic variability and diverse genetics behind these conditions. The authors emphasize the essential importance of an accurate genetic finding to guide optimal clinical care for these patients across the entire life course. As another example, a review by Cavarocchi et al.⁸ describes how the exact molecular diagnosis in asthenoteratozoospermia cases facilitates proper genetic counseling of male infertility as a sole phenotype or in association with ciliary defects. A precise genetic diagnosis has a direct consequence to the prognosis of pregnancy outcome using intracytoplasmic sperm injection (ICSI).^{8, 11}

A review by Caroselli et al.¹² introduces preconception carrier screening (CS) to identify couples at-risk of conceiving a child affected by a severe genetic disorder. This is especially important among couples seeking infertility management to become parents. For example, in case the male partner is diagnosed with obstructive azoospermia due to biallelic CFTR mutations, the female should be also referred to testing for CFTR variants. Detection of high risk through CS allows prospective parents improved reproductive decision-making, opting for preimplantation genetic testing (PGT) to select unaffected IVF embryos, donor gametes, targeted prenatal diagnosis or adoption, or taking no actions.¹²

Due to ethical reasons, studies of human male gonadal biology, spermatogenesis and implicated genes have been limited to only a few methodological options, such as histopathological analyses of available testicular biopsies. Mahyari et al. has innovatively used this material to develop a high-dimensional transcriptional atlas of the human testis at the single cell level.¹³ A review by Xu and Chen introduces spatial transcriptomics (ST)¹⁴ as a novel tool to dissect the complicated process of spermatogenesis and discusses how ST has been leveraged to identify spatially variable genes, characterize cellular neighborhood, delineate cell‒cell communications, and detect molecular changes under pathological conditions in the mammalian testis. Research on knockout (KO), transgenic, and other types of mouse models has been an indispensable tool to identify and characterize hundreds of genes required for male fertility and reproductive health. An excellent review by Singh and Schimenti¹⁵ summarizes the current outcomes and challenges in using mouse models (as a proxy to human) in reproductive biomedicine for gene discovery, functional dissection of molecular pathways, modeling putative human infertility variants, identifying contraceptive targets, and developing in vitro gametogenesis. Several papers in this Special Issue further illustrate the value of murine research to understand human reproductive conditions. For example, Yin et al.¹⁶ have summarized complementary literature from human and mouse showing the essential role of telomeres in male meiosis and Jorgez et al.¹⁷ have developed transgenic mice lacking Kctd13 to study penile development and rescue of micropenis.

Clinically actionable genetic testing of male-specific conditions is not limited to infertility diagnostics and respective management decisions. Basic research and clinical implications for male-specific cancers and their comorbidities represent another expanding area in andrology. Furthermore, a recent study has shown almost fivefold enrichment of disease-causing findings in hereditary cancer genes in infertile compared with fertile men, suggesting shared genetic etiologies.¹⁸ Prostate cancer is the most common malignancy in men, affecting one in eight subjects. A narrative review by Chou et al.¹⁹ summarizes hereditary conditions and syndromes predisposing to prostate cancer, indications for germline testing, incorporation of genetic data at different phases of cancer prevention and management, such as screening, monitoring, and treatment. Other common male-specific cancers are testicular germ cell tumors (TGCT) affecting young men due to congenital defects of testis development. Original research by Gayer et al.²⁰ describes the generated murine model of pure teratomas that can be effectively used for preclinical research of TGCT.

In summary, it is exciting to acknowledge the growing extent, diversity, and depth of androgenetics research worldwide, and its increasing role in improving clinical practice and patient management. This Special Issue has significantly contributed to highlight the current and long-term perspectives of genetics in andrology.

Maris Laan conceptualized and drafted the manuscript, and Donald F. Conrad and Kenneth I. Aston contributed to the critical commenting and editing of the material. All the authors reviewed and approved the final version.

The authors declare no conflicts of interest.