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This summary describes the association of NR6A1 (HGNC:7985) with microphthalmia, isolated with coloboma (MONDO_0000170). The association is supported by evidence from independent families demonstrating an autosomal dominant inheritance pattern. Two separate studies have reported NR6A1 variants in patients presenting with ocular malformations, including colobomatous microphthalmia, along with vertebral and renal defects, establishing a coherent genotype–phenotype correlation (PMID:39606382, PMID:39606449). The clinical presentation aligns with a specific subset of ocular abnormalities, making it a relevant consideration in diagnostic evaluation.
Genetic evidence is compelling as six independent families were identified with rare variants in NR6A1. In both studies, the same rare variant, c.274C>T (p.Arg92Trp), was observed (PMID:39606382, PMID:39606449). These families exhibited autosomal dominant inheritance with demonstrable segregation of the variant with the disease phenotype, reinforcing the association. Although additional affected relatives were not numerically detailed, consistent familial clustering across independent cohorts elevates confidence in the genetic contribution.
The variant c.274C>T (p.Arg92Trp) represents a complete coding change and has been nominated as the representative mutation for NR6A1 in this disease context. Strict adherence to HGVS nomenclature confirms the variant’s proper representation. The reported variant is not only rare in the general population but also recurrent among affected probands, further substantiating its pathogenic role. This finding supports the use of targeted genetic testing in patients with isolated microphthalmia with coloboma.
Functional assessments provide corroborative evidence for the pathogenicity of NR6A1 variants. In vitro studies utilizing cellular assays and zebrafish models have recapitulated key features of the phenotype, including abnormal ocular and somite development. Knockdown experiments showed that loss of normal NR6A1 function leads to developmental defects, and rescue studies with wild‑type mRNA—but not mutant mRNA—reinforced the variant’s deleterious effect (PMID:39606382). These experimental data highlight the critical role of NR6A1 in ocular development, consistent with a haploinsufficiency or dominant-negative mechanism.
Integrating both the genetic and functional evidence yields a robust narrative supporting a strong gene-disease association. The convergence of segregation data from six independent families and functional studies in relevant models underscores the clinical validity of NR6A1 in the etiology of microphthalmia with coloboma. This integrated evidence base exceeds the minimum threshold for a strong association, although additional supportive cases may further augment the scoring beyond the current maximum.
Key take‑home: The strong genetic and experimental evidence for NR6A1’s pathogenic role in isolated microphthalmia with coloboma provides a clinically actionable target for genetic diagnostics and personalized patient management.
Gene–Disease AssociationStrongSix independent families with segregation of the rare c.274C>T (p.Arg92Trp) variant support the association, with consistent experimental data confirming pathogenicity (PMID:39606382, PMID:39606449). Genetic EvidenceStrongThe identification of the recurrent c.274C>T (p.Arg92Trp) variant in six independent families exhibiting an autosomal dominant pattern underlines the robust genetic contribution to the phenotype. Functional EvidenceModerateFunctional assays in cellular and zebrafish models demonstrate that mutant NR6A1 fails to rescue developmental defects, corroborating the variant’s pathogenic nature. |