Roggenbuck Jennifer, Palettas Marilly, Vicini Leah, Patel Radha, Quick Adam, Kolb Stephen J
Department of Internal Medicine (J.R.) and Department of Neurology (J.R., A.Q., S.J.K.), The Ohio State University Wexner Medical Center; Department of Biomedical Informatics (M.P.), Center for Biostatistics, The Ohio State University Wexner Medical Center; College of Medicine (L.V., R.P.), The Ohio State University Wexner Medical Center; and Department of Biological Chemistry & Pharmacology (S.J.K.), The Ohio State University Wexner Medical Center, Columbus.
Neurol Genet. 2020 Jan 13;6(1):e390. doi: 10.1212/NXG.0000000000000390. eCollection 2020 Feb.
To determine the incidence of amyotrophic lateral sclerosis (ALS) genetic variants in a clinic-based population.
A prospective cohort of patients with definite or probable ALS was offered genetic testing using a testing algorithm based on family history and age at onset.
The incidence of pathogenic (P) or likely pathogenic (LP) variants was 56.0% in familial ALS (fALS); 11.8% in patients with ALS with a family history of dementia, and 6.8% in sporadic ALS ( < 0.001). expansions accounted for the majority (79%) of P or LP variants in fALS cases. Variants of uncertain significance were identified in 20.0% of fALS cases overall and in 35.7% of -negative cases. P or LP variants were detected in 18.5% of early-onset cases (onset age <50 years); the incidence of P or LP variants was not significantly different between family history types in this group.
Our data suggest that the incidence of P and LP variants in genes other than is lower than expected in Midwestern fALS cases compared with research cohorts and highlights the challenge of variant interpretation in ALS. An accurate understanding of the incidence of pathogenic variants in clinic-based ALS populations is necessary to prioritize targets for therapeutic intervention and inform clinical trial design.
确定临床人群中肌萎缩侧索硬化症（ALS）基因变异的发生率。
对一组明确或可能患有ALS的患者进行前瞻性队列研究，根据家族史和发病年龄采用检测算法进行基因检测。
家族性ALS（fALS）中致病性（P）或可能致病性（LP）变异的发生率为56.0%；有痴呆家族史的ALS患者中为11.8%，散发性ALS中为6.8%（<0.001）。在fALS病例中，扩增占P或LP变异的大多数（79%）。总体上，20.0%的fALS病例和35.7%的阴性病例中发现了意义不明确的变异。在18.5%的早发型病例（发病年龄<50岁）中检测到P或LP变异；该组中不同家族史类型的P或LP变异发生率无显著差异。
我们的数据表明，与研究队列相比，中西部fALS病例中除[具体基因]外其他基因的P和LP变异发生率低于预期，并突出了ALS中变异解读的挑战。准确了解临床ALS人群中致病性变异的发生率对于确定治疗干预靶点的优先级和为临床试验设计提供信息是必要的。
