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A recent study reported in Orphanet Journal of Rare Diseases (PMID:35606856) investigated a two‑generation hypospadias pedigree (three affected patients [PMID:35606856]) and a cohort of 49 sporadic cases. Although a novel BRAF variant was primarily highlighted in the familial case, the screening also identified candidate variants in key p38 MAPK signaling‑related genes, including TRIM67. This observation suggests that TRIM67 may contribute to hypospadias pathogenesis; however, no specific TRIM67 variant meeting HGVS criteria was described, and segregation or replication data for TRIM67 are lacking.
Functional studies in an unrelated context have shown that TRIM67 can regulate cellular pathways (notably via p53 activation in colorectal cancer PMID:31239268), but such assays have not yet been directly applied to hypospadias models. In summary, while emerging genetic signals implicate TRIM67 in hypospadias through potential disruption of p38 MAPK signaling, the current body of evidence is limited and warrants further investigation before it can be fully integrated into diagnostic decision‑making and commercial applications. Key take‑home: TRIM67 is a promising candidate for hypospadias that requires additional segregation and functional studies in relevant models.
Gene–Disease AssociationLimitedA single study (PMID:35606856) identified candidate TRIM67 variants in a pedigree (3 patients) and a cohort of 49 sporadic hypospadias patients without extensive segregation or replication data. Genetic EvidenceLimitedNo specific TRIM67 variant meeting HGVS criteria was detailed; the evidence is based solely on its inclusion as a candidate gene in a limited case series. Functional EvidenceLimitedWhile functional studies in colorectal cancer demonstrate that TRIM67 can modulate key cellular pathways (PMID:31239268), no direct functional assays have been performed to establish its role in hypospadias. |