Abstract
Purpose :
Mutations in the ABCA4 gene are the most frequent cause of inherited macular disease. To date, ~1000 disease-associated ABCA4 variants have been identified, resulting in vast genetic and phenotypic heterogeneity of ABCA4 disease. Therefore, establishing the disease prevalence and genotype/phenotype correlations is complicated. This analysis was conducted to assess the different mutation groups and the phenotypic outcome of their combinations in a large, well-characterized ABCA4 disease cohort.
Methods :
Patients (645) and family members were recruited over 18 years. Sequencing of the ABCA4 exons and non-coding sequences was performed on the Illumina TruSeq platform. Pathogenicity of variants was assessed according to the ACMG guidelines, combining information from allele frequency data in patients vs the general population, predictive algorithms (e.g., CADD), and segregation analysis in families. The analysis included only patients with two (both) ABCA4 disease-associated alleles. Mutation severity was determined through genotype frequencies in specific disease subgroups determined by age of onset and disease progression – early-onset/severe, classical, late-onset/mild.
Results :
340 different ABCA4 mutations were identified in 645 Stargardt patients. 186 (54.7%) of those were missense variants, while the other 45% included 40 (11.8%) stop mutations, 38 (11.2%) small indels, 19 (5.6%) deep intronic variants, and 57 (16.7%) splice site variants. The most frequent ABCA4 disease-associated alleles in this cohort of (mostly) European origin included: p.G1961E (23% of patients, MAF=0.12), p.N1868I (11.6%, MAF=0.06), p.[L541P;A1038V] (8.8%, MAF=0.046), p.P1380L (8.4%, MAF=0.046), p.[G863A;N1868I] (7.13%, MAF=0.037), and c.5461-10T>C (7%, MAF=0.035). The most represented allele combinations were p.[G1961E];[L541P;A1038V] (2.2% of patients), p.[G1961E];[P1380L] (1.7%), and p.[L541P;A1038V];[N1868I] (1.6%). p.G1961E and p.N1868I variants identified the two hypomorphic, late-onset groups, while patients in the early onset, severe group harbored exclusively deleterious alleles. p.P1380L, p.C54Y and some other severe variants were enriched in patients of specific ethnic origin.
Conclusions :
While ABCA4 disease is clinically and genetically very heterogeneous, (almost) definitive correlations can be made with the most frequent ABCA4 alleles and resulting phenotypes.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.