Retinal disorders

Gene: VSX2

Green List (high evidence)

Biallelic VSX2 (formerly CHX10) variants often result in microphthalmia, anophthalmia, coloboma (MAC).

PMID: 21976963 Reis et al., 2011
2 unrelated consanguineous families with AR isolated bilateral microphthalmia.
Pakistani family - affected individuals homozygous for c.668G>C (p.G223A).
Iranian family - affected individuals homozygous for c.249delG (p.Leu84SerfsX57). ERG performed on 2 sisters in this family showed inner retinal dysfunction in both.

As reviewed by Beisi Xu, there are also at least three different VSX2 variants reported in three unrelated patients with retinopathy and no reported MAC phenotype:

PMID: 36264558 Smirnov et al., 2022: 3 patients from 2 unrelated non-consanguineous Turkish families, harbouring homozygous missense variants: c.595C>T, p.(Arg199Cys) and c.698C>T, p.(Pro233Leu). All 3 patients presented with infantile nystagmus, low stable visual acuity, myopia and night blindness, cause by retinopathy with lens luxation.

PMID: 24001013 Khan et al., 2013: Case study - Female, 3yo, Saudi Arabian. Phenotype: Poor vision from birth, chorioretinal atrophy, retinal dysfunction; superior lens subluxation and smooth iris. Homozygous for c.773delA; p.(Lys258Serfs*44); variant heterozygous in unaffected brother and consanguineous parents. Homozygous frameshift BCAP29 variant also identified in patient - not much known about this gene.

Functional studies in mice and human retinal organoids indicate that the reported VSX2 variants have a variable effect on VSX2’s DNA binding properties, which may explain the phenotypic heterogeneity observed in patients (PMID: 23028343; 35831950; 38994775).
PMID: 8630490 Burmeister et al., 1996: Mice homozygous for a premature stop codon in VSX2/CHX10 are blind, with obvious microphthalmia, cataractous lens, a thin retina, and no optic nerve. Study notes that loss of VSX2CHX10 leads both to reduced proliferation of retinal progenitors and to a specific absence of differentiated bipolar cells - supportive of MAC / retinal degeneration phenotype seen in patients.

This gene is not yet associated with retinal disorders in OMIM or Gene2Phenotype.

Created: 10 Oct 2025, 2:07 p.m. | Last Modified: 10 Oct 2025, 2:18 p.m.

Panel Version: 8.39

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microphthalmia, isolated 2, OMIM:610093; retinal disorder, MONDO:0005283

Publications

• 8630490
• 21976963
• 23028343
• 24001013
• 35831950
• 36264558
• 38994775

Green List (high evidence)

since reported by Zlotogora et al. (1994, PMID:8209881), many cases with VSX2 mutant doesn't have retinal disorders.
A few recently animal models(Zebrafish and Mouse) highlighted the role of VSX2 enhancer/Super-Enhancer in Retinal Bipolar cell fates(PMIDs:23028343,25963169,31493975,32541005,35017532,35831950,38994775), could explain the heterogeneity of phenotypes in VSX2 mutants. For example, different VSX2 mutants might affect VSX2's binding at itself's Enhancers in differently.

Created: 27 May 2025, 5:18 p.m. | Last Modified: 27 May 2025, 5:18 p.m.

Panel Version: 8.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
NIGHT BLINDNESS, CONGENITAL STATIONARY, pan-bipolar cell dysfunction; LENS SUBLUXATION; Microphthalmia, isolated 2 610093; Microphthalmia/coloboma 3 610092; CATARACTS; IRIS ABNORMALITIES

Publications

• 36264558
• 24001013
• 20414678

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Red List (low evidence)

MAC gene?

Created: 30 Aug 2019, 2:12 p.m. | Last Modified: 30 Aug 2019, 2:12 p.m.

Panel Version: 1.159