Stargardt/ABCA4 disease in African Americans

Project summary/Abstract Disease-associated variation in the ABCA4 gene has emerged as the most prevalent cause of Mendelian retinal disease affecting an estimated 50,000 people in the United States. The extensive clinical heterogeneity of ABCA4-associated retinopathy, in short ABCA4-RD, which includes >40 clinical phenotypes entities (most often called Stargardt disease (STGD1), cone-rod dystrophy (CRD), retinitis pigmentosa (RP)-like, etc.), reflects its equally large genotypic profile with >2300 known disease-associated variants. While the clinical and genetic spectrum of patients of European descent has been advanced significantly since the discovery of the ABCA4 gene in 1997, the same is practically unknown for underserved minorities, especially for patients of African American (AA) descent. Only two studies have been performed in small cohorts of AA patients; therefore, the absolute majority remain uncharacterized. Therefore, it is clearly necessary to fill this serious void by comprehensive, integrated clinical and genetic analysis of ABCA4-RD in AA patients. We will test the central hypothesis that, as in our previous studies in European patients, a combination of advanced genetic screening coupled with quantitative clinical data and functional analyses of ABCA4 alleles from both coding and non-coding sequences from the entire ABCA4 locus is necessary to unequivocally determine the ABCA4- RD structure in AA patients. This program represents a collaborative effort between five centers, with demonstrated expertise in recruiting and comprehensive clinical characterization of patients, including cases of AA descent, deciphering genetic causes of ABCA4-RD, and ABCA4 functional studies. The program is organized into three Specific Aims. The first Aim is dedicated to patient recruitment and clinical analyses, research in the second Aim identifies and analyzes all variants in the entire ABCA4 locus and exome, and defines genotype-phenotype correlations, genetically defined disease subgroups and the entire structure of ABCA4 variation in AA patients. The third Aim is dedicated to functional analyses of most frequent ABCA4 alleles in AA cases by testing for their effect in structural modeling, protein function in in vitro assays, mouse models and iPS-derived retinal organoids. The proposed research will uncover and functionally verify the most frequent ABCA4 disease-associated variants in AA patients, thereby substantially advancing precise disease diagnosis, will refine clinical prognosis for ABCA4-RD caused by specific ABCA4 alleles, resulting in variable age of disease onset, expression, and progression. Integrating clinical, genetic, and functional data in the analyses and, eventually into a prediction matrix will improve diagnostic accuracy, prognostic counseling and will provide a platform for designing precise phenotype-specific treatment in clinical trials for ABCA4-RD in African Americans.