Identification of novel dystonia genes in consanguineous families

运动障碍是具有不自主运动过度或减少或其组合的神经病症。肌张力障碍是一种常见的运动障碍，其特征在于持续的肌肉收缩导致异常姿势。在儿童时期开始的许多形式的肌张力障碍具有遗传病因。然而，在肌张力障碍中存在显著的遗传异质性，具有>35个已知基因，其中突变引起孤立的、组合的或复杂的肌张力障碍综合征，使得通过常规遗传方法进行分子诊断具有挑战性。尽管下一代测序（NGS）的出现和肌张力障碍的高遗传性，肌张力障碍的病因目前在大多数患者中仍然难以捉摸。近亲家庭是丰富的患者与reckless遗传条件和识别的潜在遗传原因是在这些家庭中的便利。值得注意的是，有几个例子表明，使用这种方法鉴定的疾病基因在其他人群中也是相关的，但在其中更难以检测。在与巴基斯坦和土耳其的同事合作中，我们已经确定了大的近亲肌张力障碍家系，表明纯合基因缺陷。我们提出的项目的具体目标是：1）通过进行标准化的神经系统检查和获得生物标本，将其中12个家庭纳入研究; 2）使用外显子组测序来确定遗传原因。将通过使用桑格测序的分离分析以及通过检测其他患者和对照的候选基因内的罕见变体来验证候选变体。我们期望a）鉴定与肌张力障碍有关的新基因和B）拓宽已知基因的表型谱。这些研究可能会产生更好的诊断和治疗方案，并将提供新的信息，肌张力障碍的分子基础。

Movement disorders are neurological conditions with involuntary excess or reduction of movement or a combination thereof. Dystonia is a common movement disorder that is characterized by sustained muscle contractions resulting in abnormal postures. Many forms of dystonia that start in childhood have a genetic etiology. However, there is remarkable genetic heterogeneity in dystonia with >35 known genes, mutations in which cause isolated, combined, or complex dystonia syndromes, making molecular diagnosis by conventional genetic methods challenging. Despite the advent of next generation sequencing (NGS) and high heritability of dystonia, the etiology of dystonia currently remains elusive in the majority of patients. Consanguineous families are enriched for patients with recessively inherited conditions and the identification of the underlying genetic cause is facilitated in these families. Notably, there are several examples that disease genes that have been identified using such an approach are also relevant in other populations but are more difficult to detect therein. In collaboration with colleagues from Pakistan and Turkey, we have identified large consanguineous dystonia pedigrees suggesting a homozygous gene defect. Our specific aims for the proposed project are 1) to enroll 12 of these families into the study by performing a standardized neurological examination and obtaining biospecimens; and 2) to use exome sequencing to identify the genetic cause(s). Candidate variants will be validated by segregation analyses using Sanger sequencing and by testing other patients and controls for rare variants within the candidate genes. We expect to a) identify new genes involved in dystonia and b) to broaden the phenotypic spectrum of known genes. These studies may yield better options for diagnosis and treatment and will provide new information on the molecular basis of dystonia.