VSX2 – Microphthalmia

VSX2 variants underlie autosomal recessive microphthalmia, with homozygous and compound heterozygous alleles reported in at least four unrelated probands ([PMID:24033328]; [PMID:31884615]; [PMID:37628625]; [PMID:30181649]). Reported variants include the missense change c.667G>C (p.Gly223Arg) ([PMID:24033328]) and frameshift alleles such as c.422delA (p.Asn141IlefsTer19) ([PMID:31884615]). Affected individuals present bilateral reduction in ocular globe size with variable additional anterior segment anomalies.

Functional studies demonstrate that loss of VSX2 function causes microphthalmia. The Vsx2LacZ knock-in/knock-out mouse allele recapitulates bilateral microphthalmia, disrupted retinal layering, delayed neurogenesis, and absence of bipolar interneurons, confirming a recessive loss-of-function mechanism ([PMID:38895315]; [PMID:39610658]). Targeted mouse knock-ins of homeodomain and CVC domain mutations abolish high-affinity DNA binding and phenocopy the null phenotype, establishing the critical role of these domains in ocular development ([PMID:23028343]).

Key Take-home: VSX2 genetic testing is clinically actionable for autosomal recessive microphthalmia diagnosis and counseling.

References

• Genetic screening of AM genes in 150 patients • Year Unknown • PMID:24033328
• Advances in experimental medicine and biology • 2019 • Mutations in VSX2, SOX2, and FOXE3 Identified in Patients with Micro-/Anophthalmia PMID:31884615
• Journal of human genetics • 2018 • Identification of novel pathogenic variants and novel gene-phenotype correlations in Mexican subjects with microphthalmia and/or anophthalmia by next-generation sequencing PMID:30181649
• Genes • 2023 • Combined Single Gene Testing and Genome Sequencing as an Effective Diagnostic Approach for Anophthalmia and Microphthalmia Patients PMID:37628625
• bioRxiv • 2024 • Microphthalmia and disrupted retinal development due to a LacZ knock-in/knock-out allele at the Vsx2 locus PMID:38895315
• Eye and Brain • 2024 • Microphthalmia and Disrupted Retinal Development Due to a LacZ Knock-in/Knock-Out Allele at the Vsx2 Locus PMID:39610658
• PLoS genetics • 2012 • Vsx2 controls eye organogenesis and retinal progenitor identity via homeodomain and non-homeodomain residues required for high affinity DNA binding PMID:23028343

Evidence Based Scoring (AI generated)