Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
The association between TTC21A and male infertility (MONDO_0005372) is supported by robust genetic and functional evidence. This gene‐disease relationship follows an autosomal recessive inheritance, where bi‑allelic mutations in TTC21A disrupt spermatogenesis and lead to asthenoteratospermia, a condition marked by reduced sperm motility and abnormal sperm morphology (PMID:30929735).
Genetic evidence comes from a well‐designed study of 65 affected individuals, where TTC21A mutations were identified in three unrelated men (PMID:30929735) and further replicated by the discovery of a homozygous splicing mutation in two Tunisian cases (PMID:30929735). Segregation analysis in these families supports the autosomal recessive model. The mutation spectrum includes a range of variant classes; for instance, the missense variant c.341A>G (p.Tyr114Cys) is representative of the pathogenic changes observed.
Complementary functional studies using CRISPR-Cas9 generated Ttc21a mutant mice have revealed sperm flagellar defects and aberrant head-tail conjunction, mirroring the human phenotype of asthenoteratospermia (PMID:30929735). These experimental data provide critical support to a loss-of-function mechanism as the underlying pathogenic cause. The convergence of human genetic findings and animal model recapitulation strongly reinforces the role of TTC21A in the etiology of male infertility.
Overall, the integration of genetic discovery in multiple cohorts with rigorous functional validation confirms a strong gene-disease association between TTC21A and male infertility. While additional evidence may exist beyond the current scoring framework, the available data are sufficient to support diagnostic decision-making and to inform both commercial genetic testing panels and future academic publication.
Future studies are warranted to further delineate the complete phenotypic spectrum associated with TTC21A mutations and to assess potential modifier effects. In summary, the combined genetic and experimental evidence underscores the clinical utility of TTC21A as a critical diagnostic marker in cases of male infertility.
Gene–Disease AssociationStrongThree unrelated probands (PMID:30929735) plus replication in two additional cases and concordant mouse model data support a strong gene-disease association. Genetic EvidenceStrongFive probands with diverse pathogenic variants, including the representative missense mutation c.341A>G (p.Tyr114Cys), demonstrate robust genetic evidence consistent with autosomal recessive inheritance (PMID:30929735). Functional EvidenceStrongCRISPR-Cas9-mediated knockout studies in mice recapitulate the human asthenoteratospermia phenotype, providing strong experimental evidence for a loss-of-function mechanism (PMID:30929735). |