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.

Stargardt病（STGD1）是遗传性视网膜营养不良的一种形式，其归因于影响大型ABCA4基因功能的变异，并且可以说是最复杂的单基因疾病。对患者的治疗性试验取决于在反式中识别出因果性ABCA4变异，由于极端等位基因和临床异质性而变得复杂。我们报告了在加拿大纽芬兰的年轻遗传分离群体中STGD1的遗传结构。在过去的几十年中，基于人群的临床征募产生了29个STGD1和STGD1样家族（15个多重，14个单例）。家庭访谈和公开档案记录显示，大多数谱系创始人都是英语抽取者。全基因测序和单倍型分析产生一个高解决率（38/41病例; 92.7％）为STGD1和确定了16个致病等位基因STGD1，包括一种新颖的缺失（NM_000350.3：ABCA4 c.67-1delG）。欧洲血统的几个STGD1等位基因（包括NM_000350.3：ABCA4 c.5714 + 5G> A和NM_000350.3：ABCA4c.5461-10T> C）由于创始人效应而漂移到相对较高的人口频率。我们报告纯合患者的视网膜疾病进展，提供有价值的等位基因特异性见解。在c.5714 + 5G> A变异纯合的患者中观察到最少涉及的视网膜疾病，即所谓的“轻度”变异，在编码区和内含子/内含其他致病变异时，该变异足以沉淀STGD1表型ABCA4的外显子边界。最严重的视网膜疾病是与病例中观察到ABCA4 C [5461-10T> C。; 5603a导> T]。复杂的等位基因。我们讨论确定遗传分离物中的遗传结构的优势，以便开始应对人类遗传学的巨大挑战。