Genetic Testing in Reproductive Medicine: Advancing Diagnosis of Male and Female Infertility
Key Insights
A retrospective analysis underscores the critical role of integrating genetic testing into reproductive medicine for diagnosing infertility causes.
Whole-exome sequencing improves diagnostic yield in men with non-obstructive azoospermia (search), identifying pathogenic variants in genes such as CFAP43 (search), CFAP44, and DNAH1 (search).
Female infertility linked to oocyte/zygote/embryo maturation arrest can be elucidated through gene panel analysis targeting maternal effect genes like NLRP2 (search), NLRP5 (search), and PADI6 (search).
The integration of genetic testing into reproductive medicine is reshaping the diagnostic landscape for infertility, offering molecular clarity where traditional evaluations fall short. A growing body of evidence, synthesized from systematic reviews and clinical cohort studies, demonstrates that monogenic causes underlie a substantial proportion of both male and female infertility. These insights are driving a paradigm shift toward precision diagnostics in assisted reproduction.
The Genetic Architecture of Male Infertility
Male infertility, particularly non-obstructive azoospermia (search) (NOA), has a well-established genetic component. Houston and colleagues, in a 2020 systematic review published in Human Reproduction Update, catalogued validated monogenic causes of male infertility and highlighted emerging gene–disease relationships. Among the most clinically actionable findings are mutations in genes governing sperm flagellar structure. Khelifa et al. identified mutations in DNAH1 (search), which encodes an inner arm heavy chain dynein, as a cause of multiple morphological abnormalities of the sperm flagella (search) (MMAF). Subsequent studies expanded this genetic landscape: Sha et al. reported novel mutations in CFAP44 and CFAP43 (search) linked to MMAF, while Chen et al. demonstrated that CFAP74 variants could produce an asthenoteratozoospermia phenotype.
Whole-exome sequencing has proven transformative. Kherraf and colleagues showed that this approach improves the diagnosis and care of men with NOA, identifying pathogenic variants that directly inform clinical management. Sharifi et al. further demonstrated that genetic insights into NOA carry implications for diagnosis and testicular sperm extraction (TESE) outcomes. In a notable therapeutic development, Mashiko et al. reported successful sperm and offspring production in a NOA mouse model via testicular mRNA delivery using lipid nanoparticles, pointing toward future gene-based interventions.
Other genetic defects affect sperm function through distinct mechanisms. Mutations in CATSPER1 (search), encoding a calcium channel essential for flagellar hyperactivation, were shown by Avenarius et al. to cause male infertility. Globozoospermia, characterized by round-headed spermatozoa, is predominantly caused by DPY19L2 (search) deletions, as established by Koscinski et al. Acephalic spermatozoa syndrome has been linked to biallelic SUN5 mutations and novel PMFBP1 mutations. For men with obstructive azoospermia due to CFTR mutations, Persily et al. outlined counseling approaches and treatment options.
Female Infertility and Maternal Effect Genes
On the female side, genetic causes of infertility are increasingly recognized. Van Der Kelen and colleagues conducted a systematic review and evidence assessment of monogenic gene–disease relationships in female infertility and differences in sex development. A critical category involves maternal effect genes—genes expressed in the oocyte that govern early embryonic development. Condic reviewed the role of maternal-effect genes in mammalian development, while Mitchell provided an updated review of evidence linking these genes to birth defects.
The subcortical maternal complex (SCMC), a multiprotein structure in the oocyte, has emerged as a key player. Mu et al. identified mutations in NLRP2 (search) and NLRP5 (search) as causes of female infertility characterized by early embryonic arrest. Xu et al. demonstrated that mutations in PADI6 (search) similarly lead to early embryonic arrest. Alazami et al. reported that TLE6 mutation causes the earliest known human embryonic lethality. Bebbere and colleagues reviewed the emerging roles of the SCMC, underscoring its importance in oocyte competence.
Recurrent hydatidiform moles, another form of reproductive failure, have been linked to NLRP7 and KHDC3L mutations. Akoury et al. showed that these two maternal-effect proteins co-localize to the oocyte cytoskeleton. Reddy et al. described the genomic architecture of NLRP7 as Alu-rich, predisposing to disease-associated large deletions.
Premature ovarian insufficiency (search) (POI) represents another domain where genetics plays a decisive role. Ke et al. mapped the landscape of pathogenic mutations in POI, published in Nature Medicine, providing a comprehensive catalog of causative variants. Le Poulennec et al. examined ovarian reserve in patients with FMR1 gene premutation and highlighted the role of fertility preservation.
Clinical Translation and Counseling
The clinical utility of genetic testing extends beyond diagnosis. Lerner and colleagues articulated the value of genetic testing beyond clinical utility, emphasizing its role in providing personal and familial meaning. For couples undergoing intracytoplasmic sperm injection (ICSI), genetic diagnosis can predict outcomes. Ma et al. reported that patients with MMAF induced by novel biallelic CFAP43 (search) mutations have good fertility outcomes after ICSI. Wang et al. documented successful ICSI results in a patient with MMAF caused by a novel splicing mutation in CFAP251. Bonte and colleagues, in a 17-year retrospective study, demonstrated that assisted oocyte activation significantly increases fertilization and pregnancy outcomes in patients with low or total failed fertilization after ICSI.
The American College of Medical Genetics and Genomics (search) (ACMG) and the Association for Molecular Pathology have established standards and guidelines for the interpretation of sequence variants, providing a framework for clinical laboratories. Riggs et al. published technical standards for interpreting and reporting constitutional copy-number variants, ensuring consistency across diagnostic settings.
Methodological Advances
Technological advances underpin these clinical gains. Rajagopalan et al. developed a highly sensitive and specific workflow for detecting rare copy-number variants from exome sequencing data. Plagnol and colleagues created a robust model for read count data in exome sequencing experiments, with implications for copy number variant calling. These tools enhance the diagnostic yield of genetic testing in infertility.
The World Health Organization's laboratory manual for the examination and processing of human semen, now in its sixth edition, provides standardized protocols that complement genetic investigations. Broojeni and colleagues, reflecting on lessons learned from exome sequencing of nine infertility cases, outlined a path forward for integrating genomics into routine reproductive care.
As genetic testing becomes embedded in reproductive medicine, the ability to diagnose monogenic causes of infertility empowers clinicians to offer personalized prognoses, targeted interventions, and informed reproductive choices. The convergence of genomics, assisted reproduction, and emerging therapeutic modalities—including mRNA-based approaches—heralds a new era in the management of human infertility.