HENMT1 – Male Infertility

This summary outlines the association between HENMT1 and male infertility. HENMT1 (HGNC:26400) has been implicated in non‑obstructive azoospermia, a severe form of male infertility (MONDO_0005372). The reported data include evidence from case reports, multi‑patient studies, and functional experiments in mouse models, which together provide a coherent narrative supporting an autosomal recessive mode of inheritance (PMID:39318356, PMID:39120570).

Genetic evidence comes from a consanguineous family in which a single affected patient was identified with non‑obstructive azoospermia, and additional patients from independent cohorts also carry HENMT1 variants. In the initial case report, whole‑exome sequencing uncovered a homozygous nonsense change that disrupts the normal function of HENMT1. These findings underscore the autosomal recessive inheritance and highlight the importance of loss‑of‑function mutations in the disease mechanism (PMID:39318356).

The key variant reported is c.555G>A (p.Trp185Ter). This loss‑of‑function variant was detected in a patient with non‑obstructive azoospermia and results in premature protein truncation. The variant meets the criteria for a complete coding change and has been validated by both Sanger sequencing and functional assays in transfected cells, ensuring the integrity of the genetic finding.

Multi‑patient studies have further expanded the genetic spectrum by identifying additional HENMT1 variants, such as c.456C>G (p.Gln34Ter) and c.100C>T (p.Gln34Ter), in patients with phenotypes ranging from azoospermia to oligozoospermia (PMID:39120570). The clinical manifestations across these studies show a phenotypic continuum, where even minor differences in variant impact may correlate with variable severity of spermatogenic failure.

Functional assessments provide compelling experimental evidence that loss of HENMT1 function leads to impaired spermatogenesis. In vitro studies detected the presence of mutant HENMT1 mRNA and a truncated protein product, while in vivo mouse models replicate the human infertility phenotype with spermiogenesis arrest, deregulated LINE1 retrotransposon expression, and increased apoptosis of spermatids (PMID:39318356, PMID:39120570). These results support a mechanism of pathogenicity primarily driven by a loss‑of‑function effect which is consistent with autosomal recessive inheritance.

Integration of the genetic and functional evidence strongly supports the role of HENMT1 in the etiology of male infertility. The convergence of data from a consanguineous family, additional patient cohorts, and mechanistic studies in animal models underscores a moderately robust association. Although the number of unrelated probands is limited, the clear functional interplay between mutation, disrupted piRNA methylation, and impaired spermatogenesis highlights a critical gene‑disease relationship. The evidence, while still emerging, exceeds the minimum threshold necessary for guiding diagnostic decision‑making and further study.

Key Take‑home: HENMT1 loss‑of‑function variants, particularly c.555G>A (p.Trp185Ter), represent critical genetic determinants in male infertility and warrant integration into diagnostic pipelines for informed reproductive counseling.

References

• Andrology • 2024 • A homozygous nonsense variant in HENMT1 causes male infertility in humans and mice PMID:39318356
• Andrology • 2024 • Phenotypic continuum and poor intracytoplasmic sperm injection prognosis in patients harboring HENMT1 variants PMID:39120570

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