Structural eye disease

Gene: NR6A1

Green List (high evidence)

PMID: 40774958 Rasouly et al., 2025
Large cohort with CAKUT - NR6A1 confirmed as a CAKUT gene - described 13 total cases with predicted pathogenic heterozygous NR6A1 variants identified through exome seq.
Of 13 cases, 4 had both CAKUT and eye structural anomalies (e.g. coloboma), and 1 case had eye anomalies without CAKUT. Mix of LoF and missense variants. No spine anomalies reported in this cohort.

PMID: 41733738 Jacquinet et al., 2026
5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies (3/4 female individuals) and costovertebral defects associated with heterozygous deleterious variants in NR6A1: two inherited missense (c.1175T>G;p.(Met392Arg) and c.196C>T;p.(Arg66Cys)) as well as de novo loss of function c.439C>T, p.Gln147*. No ocular malformations reported in this cohort. Seq method: Trio WES / WES.
Functional evidence: loss of nr6a1 orthologs (a & b) in zebrafish causes skeletal anomalies (missing vertebrae) and abnormal kidney morphology.

Created: 10 Apr 2026, 11:21 a.m. | Last Modified: 10 Apr 2026, 11:21 a.m.

Panel Version: 4.43

Comment on phenotypes: OMIM phenotype updated 10th Apr 2026.

Created: 10 Apr 2026, 11:16 a.m. | Last Modified: 10 Apr 2026, 11:16 a.m.

Panel Version: 4.41

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Oculovertebral syndrome, OMIM:621277

Publications

• 40610405
• 40774958
• 41733738

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 12 Mar 2026, 3:02 p.m. | Last Modified: 12 Mar 2026, 3:02 p.m.

Panel Version: 4.39

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.

Created: 18 Jul 2025, 12:31 p.m. | Last Modified: 18 Jul 2025, 12:31 p.m.

Panel Version: 4.16

As reviewed by Siying Lin, PMID:40610405 reported six unrelated families with heterozygous rare variants (missense, nonsense, frameshift, or large deletion) in NR6A1 gene presenting with an autosomal dominant oculo-vertebral-renal (OVR) syndrome characterised by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. The variants showed incomplete penetrance and variable expressivity. Functional evidence from in silico, cellular, and zebrafish experiments showed that reported variants were either pathogenic or likely pathogenic for OVR syndrome.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.

Created: 18 Jul 2025, 12:27 p.m. | Last Modified: 18 Jul 2025, 12:27 p.m.

Panel Version: 4.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
coloboma, MONDO:0001476; microphthalmia, MONDO:0021129

Publications

• 40610405

Green List (high evidence)

PMID 40610405: 6 unrelated families with autosomal dominant syndromic form of colobomatous microphthalmia and missing vertebrae with or without congenital kidney abnormalities
Sources: Literature

Created: 4 Jul 2025, 6:56 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
microphthalmia, coloboma

Publications

• PMID: 40610405

Mode of pathogenicity
Other