Abstract
Purpose :
To assess the severity of ABCA4 variants based on phenotypic outcomes in Stargardt/ABCA4 disease patients ≥50 years of age.
Methods :
Study patients (n=80, mean age= 61.2, range 50-82 years) were selected from a large patient cohort in which two mutations were confirmed through direct sequencing of the ABCA4 locus. Affected siblings and relatives were excluded. Clinical phenotypes were assessed in 55° fundus autofluorescence (AF, 488-nm) images and full-field electroretinogram (ffERG) testing. Null alleles were defined by the PVS1 variant designation in accordance with American College of Medical Genetics (ACMG) guidelines.
Results :
Patients were cross-sectionally categorized into 4 groups based on ffERG responses and spatial severity of fleck and outer retinal atrophy: mild-intramacular (n=21, mean age=61.3), mild-extramacular (n=18, mean age=60.1), intermediate (n=11, mean age=60.1) and severe-posterior pole (n=30, mean age=62.2). Mean ages of symptomatic onset for each group were inversely correlated with increased severity. Expectedly, p.Gly1961Glu and p.Asn1868Ile variants were enriched in mild phenotypes and absent in severe cases while null alleles were enriched in severe phenotypes. Overall frequency of the p.Pro1380Leu allele was 10.6% however, its distribution was significantly skewed towards intermediate and severe phenotypes (34.8% versus 15.1%) (p<0.05). Of the 7 milder phenotype cases harboring p.Pro1380Leu, 5 were in trans with either p.Gly1961Glu or p.Asn1868Ile. The genotype p.[Pro1380Leu];[Arg1108Cys] appeared in 3 independent severe phenotype cases. Five cases homozygous for p.Ala1598Asp, Thr1019Met, p.Asp1532Asn, p.[Asp1532Asn;Asn1868Ile] and p.Asn965Ser were found in the severe phenotype group. Variants found in the mild phenotype groups harboring one null or severe allele in trans included: c.[4253+43G>A;6006-609T>A], p.Ala1038Val, p.Val989Ala and p.Ser1696Asn.
Conclusions :
In addition to null alleles, p.Pro1380Leu (including the p.[Pro1380Leu];[Arg1108Cys] genotype), p.Ala1598Asp, Thr1019Met, p.Asp1532Asn, p.[Asp1532Asn;Asn1868Ile] and p.Asn965Ser are associated with progression to a severe ABCA4 disease phenotype characterized by widespread degeneration of the posterior pole. The c.[4253+43G>A;6006-609T>A], p.Ala1038Val, p.Val989Ala and p.Ser1696Asn variants are associated with slow-progressing disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.