Background Variation in the ABCA4 gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such as age-related macular degeneration (AMD). Despite substantial progress in determining the causal genetic variation, even complete sequencing of the entire open reading frame and splice sites of ABCA4 identifies biallelic mutations in only 60%–70% of cases; 20%–25% remain with one mutation and no mutations are found in 10%–15% of cases with clinically confirmed ABCA4 disease. This study was designed to identify missing causal variants specifically in monoallelic cases of ABCA4 disease.
Methods Direct sequencing and analysis were performed in a large familial ABCA4 disease cohort of predominately European descent (n=643). Patient phenotypes were assessed from clinical and retinal imaging data.
Results We determined that a hypomorphic ABCA4 variant c.5603A>T (p.Asn1868Ile), previously considered benign due to high minor allele frequency (MAF) (~7%) in the general population, accounts for 10% of the disease, >50% of the missing causal alleles in monoallelic cases, ~80% of late-onset cases and distinguishes ABCA4 disease from AMD. It results in a distinct clinical phenotype characterised by late-onset of symptoms (4th decade) and foveal sparing (85%). Intragenic modifying effects involving this variant and another, c.2588G>C (p.Gly863Ala) allele, were also identified.
Conclusions These findings substantiate the causality of frequent missense variants and their phenotypic outcomes as a significant contribution to ABCA4 disease, particularly the late-onset phenotype, and its clinical variation. They also suggest a significant revision of diagnostic screening and assessment of ABCA4 variation in aetiology of retinal diseases.
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Contributors All the authors contributed significantly to this research. Study conceptualisation and design: RA. Sequencing: JZ. Genetic analysis and interpretation: RA and JZ. Acquisition of clinical data and specimens: WL and FTC. Clinical analysis and interpretation: WL, FTC, SHT, GF and KS. Drafting of manuscript: RA, JZ and WL. Critical revisions: All authors. All authors agree to be accountable for all aspects of the work.
Funding This work was supported, in part, by grants from the National Eye Institute/NIH EY021163, EY019861 and EY019007 (Core Support for Vision Research); Pangere Family Foundation, Pangere Center, Chicago Lighthouse, OPOS Stiftung zugunsten Wahrnehmungsbehinderten, St. Gallen, Switzerland and Alfred-Vogt-Stifung, St. Gallen, Switzerland and unrestricted funds from Research to Prevent Blindness (New York, NY) to the Department of Ophthalmology, Columbia University.
Competing interests None declared.
Patient consent All data used and presented in the study cannot be traced or identified to an individual subject. All identifiable information were removed in accordance with the Health Insurance Portability and Accountability Act of 1996 regulations and Columbia University Medical Center Institutional Review Board protocols.
Ethics approval Columbia University Medical Center Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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