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The current evidence linking ZHX3 (HGNC:15935) to type 2 diabetes mellitus (MONDO_0005148) is based on candidate gene analyses from multi‐patient studies. In a 2002 study, a genome scan in an Ashkenazi diabetic population identified a broad candidate region on chromosome 20 (PMID:12475768) that included ZHX3 among several genes. A subsequent study using exome‐array data reinforced the candidacy of ZHX3 by highlighting coding variant association signals for glycemic traits (PMID:25625282); however, no ZHX3‐specific rare or pathogenic variants were reported, and no familial segregation data have been provided. The investigation did not yield any deleterious alleles, such as a variant like c.123A>T (p.Lys41Asn) in ZHX3, leaving the genetic underpinnings based solely on association signals. More importantly, while other candidate genes in the region have been interrogated with mutation screening and functional assays, ZHX3’s role remains circumstantial without direct variant or segregation evidence. The genetic data are therefore modest and largely limited to statistical association in diverse populations.
Functional studies assessing the pathogenic mechanism of ZHX3 in type 2 diabetes are minimal. No targeted experimental evidence, such as cell‐based assays, animal models, or rescue experiments, has been reported to validate a molecular mechanism such as dominant‑negative or haploinsufficiency effects for ZHX3. Despite the inclusion of ZHX3 as a potential effector transcript in the GWAS signal analysis, there is a clear need for further functional studies and detailed familial segregation analyses to clarify its role in disease. As it stands, the association remains a candidate finding with limited clinical utility until corroborated by additional experimental and clinical evaluation. Key take‑home: Although current association signals implicate ZHX3 in type 2 diabetes mellitus, further rigorous genetic and functional studies are required to establish its utility in diagnostic decision‑making.
Gene–Disease AssociationLimitedBoth studies provide significant SNP association signals implicating ZHX3; however, no rare pathogenic variants or familial segregation data have been identified (PMID:12475768, PMID:25625282). Genetic EvidenceLimitedCandidate gene analyses show modest associations with glycemic traits, yet no direct mutation in ZHX3 was reported, precluding higher confidence in its genetic contribution. Functional EvidenceLimitedThere is a lack of targeted functional studies such as in vitro assays or animal models to confirm a pathogenic mechanism for ZHX3 in type 2 diabetes mellitus. |