Genetic characteristics of an international large cohort with Stargardt disease: The ProgStar study

Abstract

Purpose : We describe the genetic characteristics of the cohort enrolled in the international multi-center progression of Stargardt disease type 1 (STGD1) study (ProgStar) and determine ethnic features based on the allele frequency

Methods : 275 subjects with a clinical diagnosis of STGD1 and harboring multiple pathogenic ABCA4 variants were enrolled from 9 centers in the USA and Europe (ProgStar retrospective and prospective studies; Strauss et el. Ophthalmology 2016). Subjects were classified into four ethnic subgroups (European/Middle Eastern, African, Asian, and Other/Unknown) based on questionnaire responses, then comparison analysis of the allele frequency was performed with categorical testing of the independence of each prevalent allele.

Results : 195 pathogenic sequence variants were identified in the total cohort, including missense (123), splice site alteration (32), frame shift (19), stop (19), in-frame deletion (1), and large exonic deletion (1). 46 variants were novel. Exclusively missense variants were detected in 136 patients (49.5%). There were 196 European/Middle Eastern patients, 18 African (by descent), 14 Asian and 47 with other/unknown ethnicity. The three most prevalent variants in the total cohort were p.G1961E (15.3%), p.G863A (7.3%), and c.5461-10 T>C (4.9%). The three most prevalent variants in each subgroup were: p.G1961E (15.3%), p.G863A (7.9%), c.5461-10 T>C (5.9%) in European/Middle Eastern; p.R2107H (13.9%), p.V989A (8.3%), p.G991R (8.3%), p.V643M (8.3%) in African; and p.G1961E (39.3%), c.4253+4C>T (7.1%), p.S95P (7.1%) in Asian, respectively. The subgroup analysis revealed a statistically significant ethnic difference in the allele frequency of p.G1961E, p.R2107H, p.V989A, p.G991R, p.V643M, c.4253+4C>T, and p.S95P.

Conclusions : The spectrum of ABCA4 variants has now been documented in a well-characterized large cohort with STGD1. Approximately half of the cohort harbors only missense variants, which is in keeping with the relatively mild phenotype of the ProgStar cohort; since the inclusion criteria of well-demarcated macular atrophy does not include patients with very severe phenotypes such as extended atrophy. Subgroup analysis reveals the distinct prevalent alleles in each ethnicity, although the number of subjects for some subgroups is limited.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.