Homozygosity Mapping Identifies A Novel Locus For An Unusual Form Of Leber Congenital Amaurosis

Abstract

Purpose: : To identify the molecular genetic cause underlying a severe retinal dystrophy consisting of congenital blindness with nystagmus, variable severe macular colobomas and choroidal osteoma in 3 siblings of a consanguineous Vietnamese family.

Methods: : Patients were phenotyped by projected Snellen acuities, ERGs, retinal photography, in vivo microscopy (Spectralis OCT, Heidelberg), fundus autofluorescence (FAF), and kinetic perimetry. Known autosomal recessive retinitis pigmentosa and Leber congenital amaurosis (LCA) mutations (18 genes, 585 mutations) were excluded using APEX technology. We performed homozygosity mapping using 660K SNPs. Positional candidate genes were identified using the UCSC human genome browser. Bioinformatics, gene ontology, interpro domain comparisons, and gene expression profiling were performed to identify and rank functional candidates.

Results: : The three affected members had severe visual impairment ranging between counting fingers at 1 foot and hand motion vision, nystagmus and large central or ring scotomas. Fundus exam showed normal optic discs, narrow vessels, marked beaten metal changes, maculopathy and bone spicules. One patient had a peripapillary choroidal osteoma. OCT & FAF showed variable severe photoreceptor destruction, concentrated in the macular region. One patient had a deep macular coloboma. The rod-mediated ERG was not detectable, while a 5 uV cone-mediated ERG could still be recorded. The largest homozygous regions of the 3 sibs overlap on chromosome 3, in a 2.1 Mb region containing 15 genes thus far not implicated in LCA or RP. We identified 12 other retinal dystrophy patients with large homozygous regions overlapping this locus.

Conclusions: : We describe a novel retinal dystrophy phenotype in a Vietnamese family, and identified a homozygous region on chromosome 3, which does not overlap with known retinal dystrophy loci or genes. Finding this retinal dystrophy gene will improve our understanding of photoreceptor development, health and death.

Keywords: gene screening • photoreceptors • retinal degenerations: hereditary