PURPOSE To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes. METHODS One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patients ranged in age from 2 to 88 years. Analysis was focused on 441 curated genes associated with ataxia and ataxia-like conditions. RESULTS Pathogenic and suspected diagnostic variants were identified in 88 of the 170 patients, providing a positive molecular diagnostic rate of 52%. Forty-six different genes were implicated, with the six most commonly mutated genes being SPG7, SYNE1, ADCK3, CACNA1A, ATP1A3, and SPTBN2, which accounted for >40% of the positive cases. In many cases a diagnosis was provided for conditions that were not suspected and resulted in the broadening of the clinical spectrum of several conditions. CONCLUSION Exome sequencing with targeted analysis provides a high-yield approach for the genetic diagnosis of ataxia-related conditions. This is the largest targeted exome study performed to date in patients with ataxia and ataxia-like conditions and represents patients with a wide range of ataxia phenotypes typically encountered in neurology and genetics clinics.

中文翻译：

---

靶向外显子组分析确定了超过 50% 具有广泛共济失调相关表型的患者的疾病遗传基础。

目的 研究靶向外显子组方法对全国范围广泛的共济失调相关表型患者的分子诊断的影响。方法 使用靶向外显子组方法研究了从美国和加拿大各地的诊所转诊的 170 名病因不明的共济失调患者。患者年龄从 2 岁到 88 岁不等。分析集中在 441 个与共济失调和类共济失调相关的基因。结果 170 名患者中有 88 名被鉴定出致病性和疑似诊断性变异，阳性分子诊断率为 52%。涉及 46 个不同的基因，其中 6 个最常见的突变基因是 SPG7、SYNE1、ADCK3、CACNA1A、ATP1A3 和 SPTBN2，占阳性病例的 40% 以上。在许多情况下，对未被怀疑的疾病进行了诊断，从而扩大了几种疾病的临床范围。结论 带有靶向分析的外显子组测序为共济失调相关疾病的基因诊断提供了一种高产率的方法。这是迄今为止在共济失调和共济失调样疾病患者中进行的最大的靶向外显子组研究，代表了神经病学和遗传学诊所通常遇到的具有广泛共济失调表型的患者。