FSHD Genetic Modifiers

摘要 面肩肩周性肌营养不良症(FSHD)是最常见的一种 肌肉营养不良症。患有FSHD的个体在特定情况下有进行性肌肉无力 花纹，累及面部、肩部、远端腿和腿筋。FSHD的症状是 由于收缩导致DUX4同源结构域转录因子的异位表达 亚端粒D4Z4在第四染色体上重复。较大的收缩(例如，1-3个重复 (剩余的)与更严重的疾病有关，尽管这种关系很弱。 甲基化基因的突变，如Smchd1，已被证明会加剧这种严重程度 以及在没有收缩的情况下引起FSHD(FSHD2)。这些发现 提示其他基因修饰物可能会调节初级突变的严重程度。之前 评估疾病严重程度的遗传修饰物的研究一直受到小样本的限制 大小和不能控制与收缩长度相关的变化。这个 目前的提议利用具有重大历史意义的谱系来克服这些挑战。 一位患有FSHD的犹他州先驱已经有了18,181个后代。在过去的五年中，有13,424人 已知居住在犹他州，其中550人可能患有基于 常染色体显性遗传模式。先前对该家系的研究和表征 已证实该家族的收缩大小适中(重复6次)且稳定 在几代人之间。这一谱系克服了先前GWAS研究的设计挑战 给定样本大小和初级突变的控制。因此，这项建议旨在 临床上受影响的和未受影响的这个家庭成员的表型 突变的外显性和确定改变发病年龄或临床的遗传修饰物 严肃性。在目标1中，我们将招募600名家庭成员，其中一半目前 有症状。登记的参与者将提供发病年龄和临床严重程度评分。在……里面 目的2，我们将计算突变的外显率，并进行GWAS研究。一个 基于系谱的GWAS算法将用于识别那些与年龄相关的变异 发病、临床严重程度或甲基化模式改变。在目标3中，确定的修饰语将是 在建议书和初步验证中详细说明的功能模型中进行了验证 一群人。在完成时，我们将确定与所看到的可变性相关的那些变体 在FSHD。识别这些变异将允许改进临床试验设计，新的洞察力 探讨FSHD的发病机制，并寻找新的治疗靶点。 好了！

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy. Individuals with FSHD have progressive muscle weakness in a specific pattern, involving the face, shoulders, distal legs and hamstrings. The symptoms of FSHD are caused by ectopic expression of the DUX4 homeodomain transcription factor due to contraction of the subtelomeric D4Z4 repeats on chromosome 4. Larger contractions (e.g., 1-3 repeats remaining) are associated with more severe disease, though this relationship is weak. Mutations in methylation genes such as SMCHD1 have been shown to exacerbate the severity of FSHD1 as well as cause FSHD in the absence of a contraction (FSHD2). These findings suggest other genetic modifiers may modulate the severity of the primary mutation. Prior studies to evaluate genetic modifiers of disease severity have been limited by small sample sizes and inability to control for the variation associated with the length of the contraction. The current proposal utilizes a historically significant pedigree to overcome these challenges. A Utah pioneer with FSHD has had 18,181 descendants. In the past five years, 13,424 were known to be living in the state of Utah, 550 of which may have the contraction based on an autosomal dominant inheritance pattern. Prior research and characterization of this pedigree have confirmed that the contraction size is moderate in this family (6 repeats) and stable between generations. This pedigree overcomes prior design challenges for a GWAS study given the sample size and control of the primary mutation. Therefore, this proposal seeks to phenotype clinically affected and unaffected members of this family to understand the penetrance of the mutation and identify genetic modifiers that modify the age of onset or clinical severity. In Aim 1, we will enroll 600 members of the family, half of which are currently symptomatic. Enrolled participants will provide age of onset and a clinical severity score. In Aim 2, we will calculate the penetrance of the mutation and perform a GWAS study. A pedigree-based GWAS algorithm will be used to identify those variants associated with age of onset, clinical severity, or change in methylation pattern. In Aim 3, identified modifiers will be validated in functional models detailed elsewhere in the proposal and in a preliminary validation cohort. At completion, we will have identified those variants associated with the variability seen in FSHD. Identification of these variants will allow for improved clinical trial design, new insight into the pathogenesis of FSHD, and identification of novel therapeutic targets. !