KCTD13 – Hypospadias

KCTD13 has emerged as a critical candidate gene in the etiology of hypospadias, with multiple studies demonstrating that copy number deletions in this gene are strongly associated with the severity of the condition (PMID:39318621). In particular, a large-scale study in a Chinese population of 349 isolated hypospadias patients reported an 11.17% incidence of KCTD13 CNV deletion, a frequency that is markedly higher than that seen in the general population (PMID:39318621).

The overall clinical validity of the KCTD13‒hypospadias association is rated as Strong. This rating is based on robust genetic evidence collected from a sizeable patient cohort, clear genotype–phenotype correlations, and additional functional studies that demonstrate diminished nuclear androgen receptor (AR) localization in relevant animal models (PMID:36196997).

Genetically, the evidence points toward a gene dosage effect where heterozygous deletions in KCTD13 disrupt normal gu-genital development. The inheritance pattern for such CNV events is most consistent with an autosomal dominant model. A representative variant from other investigations in KCTD13 is reported as c.598G>A (p.Asp200Asn), underscoring the importance of complete coding alterations in functional assays even though the hypospadias studies primarily report CNV deletions.

Functional studies, particularly in murine models, have shown that KCTD13 haploinsufficiency results in a significant reduction in nuclear AR levels and decreased expression of downstream effectors such as SOX9, both of which are pivotal for proper genital development. These experimental findings concord with the human phenotypes observed, hence providing strong functional evidence for the role of KCTD13 in hypospadias (PMID:36196997).

While additional studies have explored KCTD13 in neuropsychiatric and metabolic contexts, the evidence specific to hypospadias is compelling with minimal conflicting data reported. The multi‐dimensional evidence—from genetic cohort studies to mechanistic functional analyses—reinforces the association between KCTD13 deletions and hypospadias.

Key Take‑Home: Integrating both genetic and functional data, KCTD13 CNV deletions constitute a powerful biomarker that can support diagnostic decision‑making and guide further clinical management in patients with hypospadias.

References

• FASEB Journal • 2022 • Gene dosage changes in KCTD13 result in penile and testicular anomalies via diminished androgen receptor function PMID:36196997
• Frontiers in Pediatrics • 2024 • Novel evidence of CNV deletion in KCTD13 related to the severity of isolated hypospadias in Chinese population PMID:39318621

Evidence Based Scoring (AI generated)