Genetic Analyses of Autosomal Recessive Choroideremia-Like Pedigrees

Abstract

Purpose: : Choroideremia (CHM) is an X-linked retinal dystrophy caused by mutations in CHM. We characterized a consanguineous Lebanese pedigree with autosomal recessive "choroideremia" and our aim was to identify a new genetic cause of CHM.

Methods: : We phenotyped the affected individuals using projected Snellen acuities, rod and cone mediated ERGs (Diagnosys LLC), retinal photography, in vivo microscopy OCT and auto-fluorescence (AF) using the SD Spectralis OCT (Heidelberg), fluorescein angiography (FA) and kinetic perimetry (Goldmann visual fields - GVF). Homozygosity mapping of four affected sibs of the family was performed with high-density SNP microarrays (Affymetrix and Illumina). We performed sequence analysis of CYP4V2.

Results: : The four affected members reported nyctalopia at age ~30. Visual acuities ranged from 20/30-20/100. ERGs ranged from ~25% remaining rod and cone b-wave amplitudes to non-detectable waves. GVF sizes ranged from 120° to non-detectable (V4e target). Retinal exam and FA were typical for CHM as fundoscopy showed choroidal sclerosis in all four affected members with normal caliber vessels and normal appearing optic discs. Homozygosity mapping revealed four homozygous regions shared by all four sibs, of which three were excluded by microsatellite analysis in the complete family. The remaining 5-Mb region on chromosome 4 encompasses CYP4V2, previously implicated in Bietti’s crystalline retinal dystrophy. A homozygous c.332T>C (p.I111T) mutation in this gene was identified in the four affected sibs. Upon clinical re-evaluation, tiny intra-retinal crystals were found in one out of four sibs. To test a broader involvement of CYP4V2 in CHM-like patients without CHM mutations, we sequenced CYP4V2 in 8 patients but did not find additional mutations.

Conclusions: : Mutations in CYP4V2 cause Bietti’s crystalline retinal dystrophy, and a highly variable form of autosomal recessive "choroideremia" without obvious crystals, although CYP4V2 mutations do not seem to be a common cause of choroideremia in patients without CHM mutations.

Keywords: gene screening • retinal degenerations: hereditary • photoreceptors