Roggenbuck Jennifer, Rich Kelly A, Vicini Leah, Palettas Marilly, Schroeder Joceyln, Zaleski Christina, Lincoln Tara, Drury Luke, Glass Jonathan D
Department of Internal Medicine (J.R.) and Department of Neurology (J.R., K.A.R.), The Ohio State University Wexner Medical Center, Columbus; The Ohio State University Wexner Medical Center (L.V.), College of Medicine, Columbus; Department of Biomedical Informatics (M.P.), The Ohio State University, Center for Biostatistics, Columbus; PreventionGenetics, LLC (J.S., C.Z., T.L., L.D.), Marshfield, WI; The Northeast ALS Consortium (NEALS) (T.L.); and Emory ALS Center (J.D.G.), Emory University School of Medicine, Atlanta, GA.
Neurol Genet. 2021 Aug 10;7(5):e615. doi: 10.1212/NXG.0000000000000615. eCollection 2021 Oct.
To report the frequency of amyotrophic lateral sclerosis (ALS) genetic variants in a nationwide cohort of clinic-based patients with ALS with a family history of ALS (fALS), dementia (dALS), or both ALS and dementia (fALS/dALS).
A multicenter, prospective cohort of 573 patients with fALS, dALS, or fALS/dALS, underwent genetic testing in the ALS Genetic Access Program (ALS GAP), a clinical program for clinics of the Northeast ALS Consortium. Patients with dALS underwent hexanucleotide repeat expansion (HRE) testing; those with fALS or fALS/dALS underwent HRE testing, followed by sequencing of , , , , and .
A pathogenic (P) or likely pathogenic (LP) variant was identified in 171/573 (30%) of program participants. About half of patients with fALS or fALS/dALS (138/301, 45.8%) had either a HRE or a P or LP variant identified in , , , , or . The use of a targeted, 5-gene sequencing panel resulted in far fewer uncertain test outcomes in familial cases compared with larger panels used in other in clinic-based cohorts. Among dALS cases 11.8% (32/270) were found to have the HRE. Patients of non-Caucasian geoancestry were less likely to test positive for the HRE, but were more likely to test positive on panel testing, compared with those of Caucasian ancestry.
The ALS GAP program provided a genetic diagnosis to ∼1 in 3 participants and may serve as a model for clinical genetic testing in ALS.
报告在全国范围内一组有肌萎缩侧索硬化症（ALS）家族史（家族性ALS，fALS）、痴呆（痴呆型ALS，dALS）或同时患有ALS和痴呆（fALS/dALS）的临床患者队列中，ALS基因变异的频率。
一项多中心前瞻性队列研究，纳入了573例fALS、dALS或fALS/dALS患者，这些患者在东北ALS联盟诊所的临床项目ALS基因访问计划（ALS GAP）中接受了基因检测。dALS患者接受六核苷酸重复扩增（HRE）检测；fALS或fALS/dALS患者先接受HRE检测，然后对C9orf72、SOD1、FUS、TARDBP和OPTN进行测序。
在573名研究参与者中，有171人（30%）被鉴定出致病性（P）或可能致病性（LP）变异。约一半的fALS或fALS/dALS患者（138/301，45.8%）在C9orf72、SOD1、FUS、TARDBP或OPTN中检测到HRE或P或LP变异。与其他基于临床队列中使用的更大的基因检测组合相比，使用靶向的5基因测序组合在家族性病例中产生的不确定检测结果要少得多。在dALS病例中，11.8%（32/270）被发现有C9orf72 HRE。与高加索血统的患者相比，非高加索地理血统的患者C9orf72 HRE检测呈阳性的可能性较小，但在组合检测中呈阳性的可能性较大。
ALS GAP项目为约三分之一的参与者提供了基因诊断，可作为ALS临床基因检测的一个范例。
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