Clinical and genetic characteristics of Stargardt disease in a large Western China cohort: Report 1

Abstract

Stargardt disease 1 (STGD1) is the most prevalent retinal dystrophy caused by pathogenic biallelic ABCA4 variants. Forty-two unrelated patients mostly originating from Western China were recruited. Comprehensive ophthalmological examinations, including visual acuity measurements (subjective function), fundus autofluorescence (retinal imaging), and full-field electroretinography (objective function), were performed. Next-generation sequencing (target/whole exome) and direct sequencing were conducted. Genotype grouping was performed based on the presence of deleterious variants. The median age of onset/age was 10.0 (5-52)/29.5 (12-72) years, and the median visual acuity in the right/left eye was 1.30 (0.15-2.28)/1.30 (0.15-2.28) in the logarithm of the minimum angle of resolution unit. Ten patients (10/38, 27.0%) showed confined macular dysfunction, and 27 (27/37, 73.7%) had generalized retinal dysfunction. Fifty-eight pathogenic/likely pathogenic ABCA4 variants, including 14 novel variants, were identified. Eight patients (8/35, 22.8%) harbored multiple deleterious variants, and 17 (17/35, 48.6%) had a single deleterious variant. Significant associations were revealed between subjective functional, retinal imaging, and objective functional groups, identifying a significant genotype-phenotype association. This study illustrates a large phenotypic/genotypic spectrum in a large well-characterized STGD1 cohort. A

Targeted next-generation sequencing identifies ABCA4 mutations in Chinese families with childhood-onset and adult-onset Stargardt disease

“…Interestingly, in our study four childhood-onset STGD families (F2, F3, F5 and F7) had more severe variants (harboring two deleterious null variants) in ABCA4 than the three adult-onset STGD families (F1, F4 and F9: harboring one null variant). These results are consistent with previous reports that individuals with truncation mutations in both of their alleles likely represent complete loss of ABCR function and the corresponding phenotype is reportedly younger onset and more severe disease (Table S3) [20,28,30,40].…”

“…Chinese patients with STGD [18], was the fourth most prevalent variant in a large western Chinese STGD1 cohort [30], and to our knowledge, has never been reported in patients of any other ethnic background. Therefore, we speculate that this may be a mutation specific to patients of Chinese ethnicity.…”

“…However, less clear agreement exists in the classification of Childhood-Onset and Adult-Onset STGD based on the age of onset [28,30]. Two childhood-onset STGD families with homozygous (F6) or heterozygous missense (F8) variants showed severe phenotypes.…”

“…Moreover, the international multicentre 'Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar)' project has led the largest genetic and clinical studies in this research area [24,25]. In addition, studies have increasingly reported on the molecular and clinical characteristics of STGD in Chinese patients [7,8,[26][27][28][29][30][31][32]. The mutation spectrum of Chinese STGD patients is reportedly quite different from that observed in other populations, with results suggesting that most of the ABCA4 mutations may be unique to Chinese patients.…”

Introduction to the special issue on Ophthalmic Genetics: Vision in 2020

“…The Global Eye Genetics Consortium has emerged as a collaborative research effort spanning Asia, India, and South America with collaborators in Europe and the USA. Two papers from Fujinami et al (2020) describe the largest series of PROM1 ‐related retinopathy and RP2 ‐related X‐linked RP in Japan, and Liu et al (2020) depict the prevalence of Stargardt‐associated pathogenic ABCA4 variants in China. Ophthalmic genetics experiences in New Zealand (Hull et al, 2020), India (Bansal et al, 2020), Brazil (Sallum et al, 2020), and Argentina, Colombia, and Chile (Daich Varela et al, 2020) outline clinical practices and molecular genetic testing algorithms in their counties.…”