Analysis of Irish Inherited Retinal Degeneration Patients with ABCA4 Gene Mutations.

Abstract

Purpose : To report on the sequence variants and the range of phenotypes found in a cohort of Irish Inherited Retinal Degenerations (IRD) patients in whom ABCA4 mutations were identified by Next Generation Sequencing (NGS).

Methods : Over 1000 retinopathy patients have been recruited to our ongoing Target 5000 NGS initiative at three sites in Dublin and Belfast. Patients are assessed using best-corrected visual acuity, Goldmann kinetic perimetry, colour vision testing, slit-lamp biomicroscopy, full field electroretinography, multifocal electroretinography, colour and autofluorescence fundus photography, and optical coherence tomography. With informed consent, DNA samples underwent exon sequencing of 254 retinopathy-associated genes using target-capture oligo panels.

Results : To date 125 patients from 114 pedigrees clinically presenting with an inherited retinal degeneration have had potentially pathogenic variants identified in ABCA4. Of these, 87 patients from 78 pedigrees had a clinical diagnosis of a “Stargardt-like maculopathy”. The remainder presented with other clinical entities including Retinitis Pigmentosa, cone-rod dystrophy and other pattern macular dystrophies not suggestive of Stargardt disease. Of these patients with non-Stargardt phenotypes 28 (73%) had two mutations identified and could be classed as patients with homozygotic or compound heterozygotic ABCA4 mutations.

Conclusions : The allelic heterogeneity of ABCA4 is well established with over 1000 pathogenic sequence variants reported to date. These mutations classically segregate with juvenile onset macular degeneration or Stargardt Disease. However, phenotypic findings are not uniform and a range of distinct clinical conditions has been reported with ABCA4 mutations. The advantage of employing a panel-based approach to genotyping inherited retinal degeneration patients, as in Target 5000, is made clear in cases such as these where unexpected identification of ABCA4 mutations resulted. This study describes the range of phenotypes and their associated ABCA4 sequence variants in the Irish population.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.