Abstract：
Macular degenerations (MDs) are a subgroup of retinal disorders characterized by central vision loss. Knowledge is still lacking on the extent of genetic and nongenetic factors influencing inherited MD (iMD) and age-related MD (AMD) expression. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease to identify associated coding and noncoding variation, however many MD patients still remain genetically unexplained. We hypothesized that the missing heritability of MDs may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. Using 17,394 smMIPs, we sequenced the coding regions of 105 iMD and AMD-associated genes and noncoding or regulatory loci, known pseudo-exons, and the mitochondrial genome in two test cohorts that were previously screened for variants in ABCA4. Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an \'\'MD-smMIPs panel,\" enabling a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets. Further analysis will identify known and novel variants in MD-associated genes to offer an accurate clinical diagnosis to patients. Furthermore, this will reveal new genetic associations for MD and potential genetic overlaps between iMD and AMD.
摘要：
黄斑变性(MD)是以中心视力丧失为特征的视网膜疾病的一个亚组。对影响遗传性MD（iMD）和年龄相关性MD（AMD）表达的遗传和非遗传因素的程度仍然缺乏了解。单分子分子反转探针（smMIP）已被证明可有效测序Stargardt病患者的ABCA4基因，以识别相关的编码和非编码变异，然而，许多MD患者仍然遗传原因不明。我们假设通过基于smMIPs的所有MD相关基因和危险因素的测序可以揭示MD的遗传力缺失。使用17,394个smMIP，我们测序了105个iMD和AMD相关基因的编码区和非编码或调节基因座，已知的伪外显子,和两个测试队列中的线粒体基因组，这些测试队列先前筛选了ABCA4中的变体。在对110位先证者进行详细测序分析后，观察到38%的诊断结果.这建立了一个\'\'MD-smMIP面板,“以高通量和具有成本效益的方式实现基因型优先的方法，同时实现跨目标的统一和高覆盖率。进一步的分析将鉴定MD相关基因中已知的和新的变体，为患者提供准确的临床诊断。此外，这将揭示MD的新遗传关联以及iMD和AMD之间潜在的遗传重叠.
