Genetics of Azoospermia

Genetics of Azoospermia

Genetic Causes of Azoospermia. Azoospermia can result from three primary etiological categories: hypothalamic-pituitary dysfunction, primary testicular failure leading to Non-Obstructive Azoospermia (NOA), and urogenital duct obstruction, termed Obstructive Azoospermia (OA). The condition is influenced by both acquired and congenital factors, with genetic contributions playing a significant role. Genetic testing, including karyotype analysis and screening for AZF microdeletions, is integral to diagnosing azoospermia, particularly NOA and OA.

Chromosomal Anomalies

1. Klinefelter Syndrome (KS): The most common genetic cause of NOA, characterized by a 47, XXY karyotype, affects testicular development and spermatogenesis. Mosaic forms of KS may allow limited sperm retrieval via testicular sperm extraction (TESE), enabling biological parenthood through assisted reproductive technologies.
2. 46, XX Testicular/Ovo-Testicular DSD: Rare and typically caused by the translocation of the SRY gene, this condition results in azoospermia due to the absence of Y-chromosome AZF regions necessary for spermatogenesis.
3. AZF Deletions: Deletions in AZFa, AZFb, or AZFc regions of the Y chromosome disrupt spermatogenesis at various stages. These microdeletions are common in idiopathic NOA cases. Genetic Causes of Azoospermia

Monogenic Causes

The application of next-generation sequencing (NGS) has expanded the understanding of monogenic defects underlying NOA. Currently, 38 candidate genes are associated with various testicular histologies, including Sertoli Cell-Only Syndrome (SCOS), maturation arrest, and hypospermatogenesis. Key genes include:

• FANCA and PLK4: Implicated in SCOS and linked to DNA repair pathways and centriole duplication, respectively.
• MEI1, TEX11, and STAG3: Critical for meiotic chromosome pairing and crossing-over, mutations in these genes result in spermatogenic arrest.
• TDRD7 and ZMYND15: Play roles in post-meiotic regulation, with disruptions causing late-stage spermatogenic failure.

Syndromic Associations

Certain syndromes, such as Congenital Hypogonadotropic Hypogonadism (CHH) and Congenital Bilateral Absence of Vas Deferens (CBAVD), are linked to specific genetic mutations:

• CHH: Involves over 40 genes affecting GnRH production, leading to azoospermia. Gonadotropin therapy can restore fertility in many cases.
• CBAVD: Associated primarily with CFTR mutations, genetic testing of both partners is essential due to the high carrier rate in the population.

Implications for Clinical Practice

Advances in genetic understanding have improved diagnostic accuracy, patient counseling, and treatment strategies. Genetic testing guides the choice of interventions such as TESE or sperm cryopreservation. It also informs discussions on inheritance risks and the use of preimplantation genetic testing in assisted reproduction.

Future research aims to refine the genetic basis of idiopathic NOA, identify novel candidate genes, and integrate these findings into routine diagnostic workflows to enhance patient care.