Pathogenic variants in GALNT3, GALNT8, and GALNTL5 are associated with distinct sperm defects in human asthenoteratozoospermia.

OBJECTIVE

To investigate the contribution of variants in the GALNT gene family to male infertility and to evaluate the outcomes of intracytoplasmic sperm injection (ICSI) in infertile patients carrying GALNT variants.

DESIGN

Genetic case-control study with functional validation and assisted reproductive technology follow-up.

SUBJECTS: A total of 1,148 men with asthenoteratozoospermia and 678 fertile male controls from a Southwest Chinese population recruited between 2018 and 2024.

EXPOSURE: Variants in the GALNT gene family identified by whole-exome sequencing and classified according to American College of Medical Genetics and Genomics (ACMG) guidelines.

MAIN OUTCOME MEASURES: GALNT variant profile and ACMG-based pathogenicity classification; sperm morphological and ultrastructural defects assessed by immunofluorescence staining and electron microscopy; ICSI outcomes.

RESULTS

Infertile men carried a significantly higher number of GALNT variants per individual than fertile controls. Moreover, potentially deleterious GALNT variants were exclusively present in infertile patients. GALNT3 mutations were associated with globozoospermia, GALNT8 mutations with severe flagellar abnormalities characterized by loss of the central microtubule pair, and GALNTL5 mutations with combined sperm head and tail defects. Mutant GALNT proteins showed markedly reduced or absent expression. Distinct localization patterns were observed for GALNT3 (sperm acrosome), GALNT8 (sperm flagellum), and GALNTL5 (sperm head and flagellum). ICSI outcomes were comparable between patients carrying GALNT variants and controls.

CONCLUSIONS

Our study suggests a potential contribution of GALNT variants to male infertility and provides the first evidence implicating GALNT3 and GALNT8 variants in human asthenoteratozoospermia. ICSI represents a favorable reproductive strategy for infertile patients carrying GALNT variants.