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

Abstract

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 in silico 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.

Keywords: genetics; macula; retina.

Figure 1

The distribution of variants and genotype groups of cases with Stargardt disease 1 (STGD1) recruited to the Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) studies. (A) Distribution of 245 variants detected in the total cohort of 345 patients: 245 variants were identified in the total cohort including missense variants (n=152), intronic variants in splice regions with predicted splice site alteration (n=34), stop (n=19), frame shift (n=18), deep intronic variants with uncertain effect (n=7), exonic synonymous with potential splice site alteration (n=4), intronic variants in splice region with potential splice site alteration (n=3), missense variants with significant splice site alteration (n=3), exonic synonymous variants with significant splice site alteration (n=1), missense variants with uncertain effect (n=1), large exonic deletion (n=1), in-frame deletion (n=1) and duplication (n=1). (B) Distribution of 211 likely pathogenic variants: 211 likely pathogenic variants comprising missense variants (n=133), intronic variants in splice regions with significant splice site alteration (n=34), stop (n=19), frame shift (n=18), missense variants with significant splice site alteration (n=3), exonic synonymous variants with significant splice site alteration (n=1), large exonic deletion (n=1), in-frame deletion (n=1) and duplication (n=1). (C) Distribution of 50 novel likely pathogenic variants: 50 likely pathogenic variants were novel, including missense variants (n=27), intronic variants in splice regions with significant splice site alteration (n=12), frame shift (n=7), stop (n=3) and duplication (n=1). (D) Distribution of genotype groups in 279 patients with multiple likely pathogenic variants: 279 patients harbouring multiple likely pathogenic variants were classified into three genotype groups based on the severity of predicted mutational damage: genotype group A with two or more severe/null variants (n=16), genotype group B with one severe/null variant and at least one missense or in-frame insertion/deletion variant (n=124) and genotype group C with two or more missense or in-frame insertion/deletion variants (n=139).

Figure 2

Geographical subgroup analysis of allele frequency in 23 prevalent likely pathogenic variants between four nations. Two hundred and seventy-nine patients harbouring multiple likely pathogenic consists of 121 patients from the USA, 71 from UK, 52 from France and 35 from Germany and comparison analysis revealed statistical difference in nine variants (†).