Faculty of Medicine, Memorial University, St. John's, NL, A1B 3V6, Canada.
Eastern Health Corporation, St. John's, NL, A1B 3V6, Canada.
Eur J Hum Genet. 2020 Jul;28(7):925-937. doi: 10.1038/s41431-020-0581-4. Epub 2020 May 28.
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.
斯塔加特病（STGD1）是一种遗传性视网膜营养不良，归因于影响大型 ABCA4 基因功能的变异，可说是最复杂的单基因疾病。患者的治疗试验取决于鉴定跨等位基因的因果 ABCA4 变异，这受到极端等位基因和临床异质性的影响。我们报告了加拿大纽芬兰年轻遗传隔离人群中 STGD1 的遗传结构。几十年来基于人群的临床招募产生了 29 个 STGD1 和 STGD1 样家族（15 个多重，14 个单一）。家族访谈和公共档案记录显示，绝大多数系谱创始人都有英国血统。全基因测序和单倍型分析为 STGD1 提供了高解决率（38/41 例；92.7%），并确定了 16 个致病 STGD1 等位基因，包括一个新的缺失（NM_000350.3：ABCA4 c.67-1delG）。几个起源于欧洲的 STGD1 等位基因（包括 NM_000350.3：ABCA4 c.5714+5G>A 和 NM_000350.3：ABCA4 c.5461-10T>C）由于奠基者效应而漂移到相对较高的人群频率。我们报告了纯合子患者的视网膜疾病进展情况，提供了有价值的等位基因特异性见解。在纯合子患者中，观察到涉及最少的视网膜疾病，这些患者携带 c.5714+5G>A 变体，这是一种所谓的“轻度”变体，在 ABCA4 编码区和内含子/外显子边界没有其他致病性变体的情况下足以引发 STGD1 表型。在携带 ABCA4 c.[5461-10T>C；5603A>T]复合等位基因的病例中观察到最严重的视网膜疾病。我们讨论了确定遗传隔离人群遗传结构的优势，以便开始应对人类遗传学的重大挑战。
