Precision medicine for ABCA4 disease: modifier alleles

影响ABCA 4蛋白结构和功能的遗传变异引起了广泛的收集 遗传和临床异质性疾病，统称为ABCA 4疾病， 以表型重叠和可变的遗传率和表现力为特征。某些表型变异 可以归因于高度外显ABCA 4突变的变异性;然而， 不能仅用这些突变来解释：1）许多患者具有完全相同的ABCA 4突变 有不同的表型，包括~67%的家族性病例在一个时期内具有时间不一致的表型。 一代2)属于不同种族的患者即使具有相同的表型也具有不同的表型。 突变。3)ABCA 4疾病的特征性特征在严重程度、发病时间和预后方面广泛变化。 预后结果导致沿着沿着不同疾病轨迹进展的几种亚表型。四、 ABCA 4疾病的小鼠模型具有可变的脂褐素积累表型，这取决于基因表达。 背景 精准医学的新兴概念要求识别与以下疾病相关的所有遗传变异： 特定疾病表型。虽然ABCA 4疾病的遗传分析已经取得了实质性进展，但 明确诊断和准确评估疾病预后仍远未达到100%有效率。最 重要的是，改变ABCA 4疾病的极端异质性表现的遗传变异， 几乎无人知晓我们将测试两个特定的假设：1）一些（常见的）ABCA 4变异代表 极端亚型等位基因和/或修饰物，其仅在某些情况下与疾病相关。 条件2)顺式和反式作用的遗传变异超出了高度渗透突变， ABCA 4疾病的表达。 这项研究计划，基于大规模的，全面的临床和遗传特征的家庭， ABCA 4疾病的队列，积累的数据和知识，以确定和功能分析的变异， ABCA 4基因座采用人和小鼠相结合的遗传分析方法，包括两个特异性 目标。在第一个目标中，我们增加并完善了我们的ABCA 4疾病患者队列， 方法使用这个和其他群组来鉴定ABCA 4疾病在基因座中的其他遗传修饰物， 在基因组中。在第二个目标中，我们将通过补充方法确定ABCA 4修饰符 利用多样性远系小鼠作图资源。这些研究的结果将大大 提高基因检测和疾病预后评估的准确性，并将提供 用于发现疗法的综合平台以及临床试验设计和结构的蓝图。

Genetic variation affecting the structure and function of the ABCA4 protein gives rise to a broad collection of genetically and clinically heterogeneous diseases, known collectively as ABCA4 disease, which are characterized by both phenotypic overlap and variable penetrance and expressivity. Some phenotypic variation can be attributed to variability of highly penetrant ABCA4 mutations; however, much of the heterogeneity cannot be explained by such mutations alone as: 1) Many patients with exactly the same ABCA4 mutations have different phenotypes, including ~67% of familial cases with temporally discordant phenotypes within a generation. 2) Patients belonging to various ethnic groups have different phenotypes even with the same mutations. 3) The pathognomonic features of ABCA4 disease vary extensively in severity, time of onset and prognostic outcome resulting in several sub-phenotypes that progress along different disease trajectories. 4) Mouse models of ABCA4 disease have variable lipofuscin accumulation phenotype depending on the genetic background. The emerging concept of Precision Medicine requires identification of all genetic variation associated with specific disease phenotypes. While the genetic analyses of ABCA4 disease have substantially advanced, an unequivocal diagnosis and accurate assessment of disease prognosis are still far from 100% efficiency. Most importantly, the genetic variation modifying the extremely heterogeneous presentation of ABCA4 disease is practically unknown. We will test two specific hypotheses: 1) Some (frequent) ABCA4 variants represent extremely hypomorphic alleles and/or modifiers, which are associated with the disease only under certain conditions. 2) Both cis- and trans-acting genetic variation beyond highly penetrant mutations modifies the expression of ABCA4 disease. The research program, based on large, comprehensively clinically and genetically characterized familial cohort of ABCA4 disease, accumulated data and knowledge to identify and functionally analyze variants in the ABCA4 locus by using a combination of human and mouse genetic analysis methods, includes two Specific Aims. In the first Aim, we increase and refine our cohort of ABCA4 disease patients with clinical and genetic methods use this and other cohorts to identify additional genetic modifiers of ABCA4 disease in the locus and across the genome. In the second Aim we will determine ABCA4 modifiers by a complementary approach utilizing the Diversity Outbred mouse mapping resource. The outcome of these studies will substantially improve the accuracy of genetic testing and prognostic assessment of the disease, and will provide a comprehensive platform for discovering therapies and blueprint for the design and structure of clinical trials.