ARMC2 – Male Infertility

This summary evaluates the association between ARMC2 (HGNC:23045) and male infertility (MONDO_0005372), a condition characterized by multiple morphological abnormalities in sperm flagella. Two independent studies have reported homozygous variants in ARMC2 that co-segregate with asthenoteratospermia in affected individuals from diverse families (PMID:38492154; PMID:30686508). The evidence spans both case reports and multi‐patient studies, providing a robust clinical context for the gene–disease relationship. The disease phenotype directly impacts sperm structure and function, correlating with the molecular defects observed. In addition, the studies used comprehensive sequencing and phenotypic analyses to characterize the variants. Overall, the collective clinical observations support a meaningful and reproducible association.

The clinical validity of the ARMC2–male infertility association is rated as Strong. The 2024 study identified affected individuals from two unrelated Han Chinese families (PMID:38492154), and the 2019 study reported five unrelated affected individuals (PMID:30686508) with similar sperm flagellar abnormalities. This cumulative evidence, based on independent genetic findings and segregation analyses, reinforces the genetic contribution of ARMC2 in male infertility. Consistent phenotype presentation across different cohorts further validates the association. Experimental data complement these genetic insights, enhancing the overall clinical interpretation. Multiple lines of evidence converge to support the strong validity category.

Genetic evidence demonstrates that ARMC2 follows an autosomal recessive inheritance pattern. Reported variants include both missense and frameshift mutations that disrupt protein function. For example, the variant selected for this summary is c.314C>T (p.Pro105Leu), a homozygous missense change observed in affected patients (PMID:38492154). Additional variants noted include frameshift and splice alterations that further substantiate the gene’s involvement. The consistent identification of segregating variants in affected individuals supports a direct genetic causality. This spectrum of variant types underscores the intrinsic molecular heterogeneity of the disorder.

Functional and experimental evidence corroborates the pathogenicity of ARMC2 variants. In vitro assays using HEK293T cells revealed a modest increase in protein expression that correlated with abnormal sperm flagellar morphology. Moreover, immunostaining analyses showed a frequent absence of the central pair complex, a critical axonemal component in proper flagellar assembly (PMID:30686508). Animal models, including CRISPR-Cas9 engineered Armc2-mutant mice, displayed phenotypes consistent with human MMAF. These findings illuminate the mechanistic underpinnings by which ARMC2 disruption leads to defective flagellum structure. As a result, functional studies provide important biological context supporting the genetic findings.

No significant conflicting evidence has been reported to date regarding the role of ARMC2 in male infertility. Both clinical and functional studies exhibit strong concordance, and alternative phenotypic explanations have not supplanted the current gene–disease model. The absence of contradictory reports further consolidates the validity of the association. Continued investigation may uncover additional genetic modifiers; however, the current evidence exceeds the ClinGen scoring maximum. This uniformity in evidence enhances the confidence in diagnostic decision-making.

In conclusion, the integrated clinical, genetic, and experimental data robustly establish ARMC2 as a strong candidate causative gene for male infertility with multiple morphological abnormalities of the sperm flagella. The autosomal recessive inheritance and diverse variant spectrum underscore its clinical utility in genetic testing and patient management. This association offers valuable insights for diagnostic evaluations and potential therapeutic stratification in cases of infertility. Key take‑home: ARMC2 variant screening is critical for effective diagnosis and management of genetically determined male infertility.

References

• Journal of assisted reproduction and genetics • 2024 • Identification of novel homozygous asthenoteratospermia‑causing ARMC2 mutations associated with multiple morphological abnormalities of the sperm flagella. PMID:38492154
• American journal of human genetics • 2019 • Bi-allelic Mutations in ARMC2 Lead to Severe Astheno‑Teratozoospermia Due to Sperm Flagellum Malformations in Humans and Mice. PMID:30686508

Evidence Based Scoring (AI generated)