Abstract
Purpose :
To describe the phenotype-genotype correlation on a cohort of individuals with homozygous disease-associated ABCA4 variants.
Methods :
Twenty-two affected individuals from 15 families ascertained from a total cohort of 434 families with Stargardt disease presenting to a single center. A detailed history was obtained, and color fundus photography, fundus autofluorescence imaging, optical coherence tomography, and electrophysiologic assessment were performed. ABCA4 mutations were detected through targeted capture and next-generation sequencing.
Results :
Twenty-two (27,8%) patients with homozygous ABCA4 variants were selected among 79 patients who had undergone molecular testing for Stargardt disease.
Five disease-associated homozygous ABCA4 alleles were identified, including one intronic variant causing splice-site alteration and two complex alleles: p.T1346fs , p.Arg602Trp, c.-2591G>A, p.His1941Pro and p.Leu1350Leu , p.S1642R and p.Val1682_Val1686del. The complex alleles p.His1941Pro and p.Leu1350Leu have not been reported previously. The most frequent pathogenic variant in this cohort was p.Arg602Trp (11/23 patients).
Nineteen patients with homozygous alleles had early-onset (<10 years) disease and a severe phenotype: 8 patients from 4 families with p.T1346fs, 11 patients from 8 families p.Arg602Trp and two patients homozygous for the complex alleles: one patient presenting the novel complex allele p.His1941Pro and p.Leu1350Leu and one patient p.S1642R and p.Val1682_Val1686del. The patient homozygous for the complex allele p.S1642R and p.Val1682_Val1686del presented the most precocious disease. One patient with homozygous intronic c.-2591G>A had adult-onset disease and a mild phenotype, with a spared fovea and long preserved visual acuity.
Conclusions :
The study of the phenotypic features of patients with homozygous ABCA4 alleles allows a detailed clinical assessment of the effect of each individual allele on retinal structure and function. The common alleles identified, p.T1346fs and p.Arg602Trp, both have a severe structural and functional effect on human retina. The complex allele p.S1642R and p.Val1682_Val1686del is related to an early and severe disease. The new complex allele p.His1941Pro and p.Leu1350Leu is related to a severe phenotype of Stargardt disease. The intronic c.-2591G>A is associated with relatively long retained photoreceptor architecture and function at the fovea.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.