KIAA0825 – Postaxial Polydactyly

This summary evaluates the association between KIAA0825 (HGNC:28532) and postaxial polydactyly (MONDO_0020927). Multiple studies converge on autosomal recessive inheritance with several families demonstrating co-segregation of pathogenic variants with the limb malformation phenotype. The evidence spans case reports, multi‐patient genetic analyses, and functional assessments, underpinning the role of KIAA0825 in limb development (PMID:32147526, PMID:30982135).

Clinical evidence is robust with reports from at least four unrelated probands. In one study, a consanguineous Pakistani family exhibited a novel homozygous missense variant, while other studies identified compound heterozygous splice variants and frameshift/nonsense mutations; all findings reveal consistent segregation of the variants with the phenotype (PMID:32147526, PMID:35886013). Such multi‐family segregation and cross‐study consistency have been instrumental in establishing the gene‐disease association as strong.

Genetic evidence is further strengthened by the diversity of variant types observed. The reported variant c.50T>C (p.Leu17Ser) is a representative finding that complies with standard HGVS notation. In addition to this missense change, splice site and loss‐of‐function variants have been identified in independent families, confirming the genetic heterogeneity underlying postaxial polydactyly (PMID:32147526, PMID:35886013). Segregation analyses in these studies reinforce autosomal recessive inheritance, with affected relatives in the examined families co‐segregating the mutant alleles.

Functional studies provide moderate supportive evidence for the pathogenicity of KIAA0825 variants. In vitro splicing assays and protein structural analyses have demonstrated that the identified splice site variants and the missense variant trigger deleterious effects on transcript processing and protein folding, respectively. These experimental data corroborate the clinical findings by linking the molecular deficits to abnormal limb patterning during development (PMID:35886013).

No substantial conflicting evidence has been reported. Although one study identified a co‐existing variant in another gene, the collective genetic and functional data overwhelmingly support KIAA0825’s role in postaxial polydactyly. The consistency across multiple independent reports further consolidates the clinical utility of testing for KIAA0825 variants in patients with this phenotype.

Key Take‑home: The strong integration of genetic and functional evidence confirms that pathogenic variants in KIAA0825 are strongly associated with autosomal recessive postaxial polydactyly, thereby enhancing diagnostic decision‑making and clinical management.

References

• Genomics • 2020 • Identification of a novel biallelic missense variant in the KIAA0825 underlies postaxial polydactyly type A PMID:32147526
• Genes • 2022 • Prenatal Detection of Novel Compound Heterozygous Splice Site Variants of the KIAA0825 Gene in a Fetus with Postaxial Polydactyly Type A PMID:35886013
• Human Genetics • 2019 • Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly PMID:30982135

Evidence Based Scoring (AI generated)