Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK.
Human Genetics, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
J Neurol Neurosurg Psychiatry. 2021 May;92(5):510-518. doi: 10.1136/jnnp-2020-325014. Epub 2021 Feb 14.
The clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care.
We performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases.
21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074).
Routine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.
在肌萎缩侧索硬化症（ALS）中常规进行基因测序的临床实用性尚不确定。我们的目的是确定常规对 44 个与 ALS 相关的基因进行靶向测序是否会对疾病分类和临床护理产生重大影响。
我们对英国谢菲尔德运动神经元疾病诊所连续招募的 100 例 ALS 患者前瞻性病例系列进行了 44 个基因panel 的靶向测序。所有参与者均由专家顾问神经病学家诊断为 ALS。7/100 例患者有家族性 ALS，但大多数为明显的散发性病例。
21%的 ALS 患者携带已确认的致病性或可能致病性突变，其中 93%无 ALS 家族史。15%符合当前 ALS 基因治疗试验的纳入标准。21%的致病性突变患者伴有另一个意义不明的变异（VUS）。在 ALS 相关基因中，另有 21%的 ALS 患者携带 VUS。总体而言，13%的患者携带一种以上的遗传变异（致病性或 VUS）。携带两种变异的 ALS 患者的发病年龄明显早于携带单一变异的患者（发病中位年龄=56 岁 vs 60 岁，p=0.0074）。
在专门的 ALS 转诊诊所中对 ALS 相关致病性突变进行常规筛查将影响 21%病例的临床护理。在去除非特异性或预测良性变异后，ALS 基因panel 中另外 21%的患者具有尚未确认意义的变异。总体而言，已知 ALS 相关基因内的变异在 42%的患者中具有潜在的临床重要性。
