Lens Subluxation and Retinal Dysfunction in a Girl with Homozygous VSX2 Mutation

Abstract

Objective: To describe a unique lens subluxation phenotype in a child from a consanguineous family and to determine its genetic basis.

Methods: Ophthalmologic examination (including ocular biometry and electroretinography [ERG] for the proband) and autozygosity-analysis-guided exome sequencing for the family; confirmatory candidate gene sequencing in the family and ethnically matched controls.

Results: An otherwise healthy 3-year-old Saudi Arabian girl with poor vision since birth had smooth irides, lens subluxation, cone-rod dysfunction, and high myopia – features resembling Knobloch syndrome but differing in regard to direction of lens subluxation (superior rather than temporal) and the pattern of chorioretinal atrophy (without vitreous condensations or distinct macular atrophy). Autozygome-guided exome sequencing revealed the girl to harbor a homozygous exon 5 mutation in the ocular transcription factor gene visual homeobox 2 (VSX2) [c.773delA; p.Lys258SerfsX44] that was heterozygous in the unaffected brother and parents and absent in 100 healthy ethnically matched controls and on-line databases. Previously reported VSX2 mutations have affected the DNA-binding domains and only been associated with microphthalmia. Unlike previously reported mutations, the current VSX2 mutation is downstream to the protein’s DNA binding domains.

Conclusions: The phenotype of this girl is unique and suggests a normal regulatory role for VSX2 in iris, zonule, and cone-rod development. For a consanguineous family with suspected recessive ocular disease but without a clear candidate gene, autozygome-guided exome analysis is a powerful technique, even when only a single patient is affected.

• Cone-rod
• ectopia lentis
• Knobloch syndrome
• VSX2

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This study was funded in part by a KACST grant (08-MED497-20) to FSA. The funding organization had no role in the design or implementation or analysis of the study.

Notice of Correction:

Changes have been made to this article since its original online publication date of August 20, 2013.