The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate
| Autor: | Terry-Lynn Young, Darren D. O’Rielly, Jim Houston, Justin A. Pater, Donna Bautista, Jane Green, Hoda Rajabi, James Whelan, Nelly Abdelfatah, Tammy Benteau, Amy Sheaves, Dante Galutira |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Population ABCA4 Article Gene Frequency Genetics medicine Humans Stargardt Disease Allele education Genetics (clinical) education.field_of_study biology Haplotype Homozygote medicine.disease Human genetics Founder Effect Pedigree Stargardt disease Mutation biology.protein ATP-Binding Cassette Transporters Female Genetic isolate Founder effect |
| Zdroj: | Eur J Hum Genet |
| Popis: | Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 variants in trans, which is complicated by extreme allelic and clinical heterogeneity. We report the genetic architecture of STGD1 in the young genetically isolated population of Newfoundland, Canada. Population-based clinical recruitment over several decades yielded 29 STGD1 and STGD1-like families (15 multiplex, 14 singleton). Family interviews and public archival records reveal the vast majority of pedigree founders to be of English extraction. Full gene sequencing and haplotype analysis yielded a high solve rate (38/41 cases; 92.7%) for STGD1 and identified 16 causative STGD1 alleles, including a novel deletion (NM_000350.3: ABCA4 c.67-1delG). Several STGD1 alleles of European origin (including NM_000350.3: ABCA4 c.5714 + 5G>A and NM_000350.3: ABCA4 c.5461-10T>C) have drifted to a relatively high population frequency due to founder effect. We report on retinal disease progression in homozygous patients, providing valuable allele-specific insights. The least involved retinal disease is seen in patients homozygous for c.5714 + 5G>A variant, a so-called “mild” variant which is sufficient to precipitate a STGD1 phenotype in the absence of other pathogenic variants in the coding region and intron/exon boundaries of ABCA4. The most severe retinal disease is observed in cases with ABCA4 c.[5461-10T>C;5603A>T] complex allele. We discuss the advantages of determining genetic architecture in genetic isolates in order to begin to meet the grand challenge of human genetics. |
| Databáze: | OpenAIRE |
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