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Abstract：
Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.
摘要：
遗传性黄斑营养不良（iMDs）是一组遗传性疾病，影响视网膜的中心区域。为了研究iMDs的遗传基础，我们使用单分子分子逆转探针对1352例诊断为iMDs的黄斑病变相关基因进行测序.在这个群体中，39.8％的患者被认为是由49个不同基因中的460个不同变异的遗传解释，其中73个是新变异。一些影响拼接。前五名最常见的致病基因是ABCA4（37.2%），PRPH2（6.7%），CDHR1（6.1%），PROM1（4.3%）和RP1L1（3.1%）。有趣的是,几乎三分之一的患者（28.1%）发现了外显率不完全的变异，因此,部分患者可能无法仅通过报告的变异来解释.除CDHR1：c.783G>A和CNGB3：c.188G>A外，还包括八个先前报道的外显率不完全的变体。值得注意的是,不常规进行变异定相分离分析-这是一个限制，这也可能影响整体诊断率。Therelativelyhighprobandsofprobandswithoutanyputativecausativevariant(60.2%)highlightstheneedtoexplorevariantswithcompletelypenetrance,疾病的潜在修饰因子以及iMDs和年龄相关性黄斑变性之间的遗传重叠。我们的结果为iMDs的遗传前景提供了有价值的见解，并值得未来探索以确定其他黄斑病变基因的参与。
