Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.

TitleDetailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.
Publication TypeJournal Article
Year of Publication2019
AuthorsFujinami, K, Strauss, RW, Chiang, JPei-Wen, Audo, IS, Bernstein, PS, Birch, DG, Bomotti, SM, Cideciyan, AV, Ervin, A-M, Marino, MJ, Sahel, J-A, Mohand-Said, S, Sunness, JS, Traboulsi, EI, West, S, Wojciechowski, R, Zrenner, E, Michaelides, M, Scholl, HPN
Corporate AuthorsProgStar Study Group, ProgStar Study Group
JournalBr J Ophthalmol
Date Published2019 03
KeywordsAdolescent, Adult, Age of Onset, Aged, ATP-Binding Cassette Transporters, Child, Child, Preschool, Cohort Studies, Databases, Factual, DNA Mutational Analysis, Female, Gene Frequency, Genotyping Techniques, Geography, Humans, Internationality, Macular Degeneration, Male, Middle Aged, Mutation, Polymerase Chain Reaction

BACKGROUND/AIMS: To describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.

METHODS: 345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.

RESULTS: 211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.

CONCLUSIONS: There is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

Alternate JournalBr J Ophthalmol
PubMed ID29925512
PubMed Central IDPMC6579578
Grant ListR01 EY009076 / EY / NEI NIH HHS / United States
R01 EY013203 / EY / NEI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
P30 EY014800 / EY / NEI NIH HHS / United States