Amyotrophic Lateral Sclerosis Genetic Access Program: Paving the Way for Genetic Characterization of ALS in the Clinic,Neurology Genetics

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Amyotrophic Lateral Sclerosis Genetic Access Program: Paving the Way for Genetic Characterization of ALS in the Clinic
Neurology Genetics ( IF 3.0 ) Pub Date : 2021-10-01 , DOI: 10.1212/nxg.0000000000000615
Jennifer Roggenbuck ₁ , Kelly A Rich ₁ , Leah Vicini ₁ , Marilly Palettas ₁ , Joceyln Schroeder ₁ , Christina Zaleski ₁ , Tara Lincoln ₁ , Luke Drury ₁ , Jonathan D Glass ₁

Affiliation

Objective

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).

Methods

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 C9orf72 hexanucleotide repeat expansion (HRE) testing; those with fALS or fALS/dALS underwent C9orf72 HRE testing, followed by sequencing of SOD1, FUS, TARDBP, TBK1, and VCP.

Results

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 C9orf72 HRE or a P or LP variant identified in SOD1, FUS, TARDBP, TBK1, or VCP. 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 C9orf72 HRE. Patients of non-Caucasian geoancestry were less likely to test positive for the C9orf72 HRE, but were more likely to test positive on panel testing, compared with those of Caucasian ancestry.

Conclusions

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.

中文翻译：

肌萎缩侧索硬化症遗传获取计划：为临床上 ALS 的遗传表征铺平道路

客观的

报告肌萎缩侧索硬化症 (ALS) 基因变异在全国范围内具有 ALS (fALS)、痴呆 (dALS) 或 ALS 和痴呆 (fALS/dALS) 家族史的临床患者队列中的频率。

方法

一个由 573 名 fALS、dALS 或 fALS/dALS 患者组成的多中心前瞻性队列在 ALS 遗传访问计划 (ALS GAP) 中接受了基因检测，这是一项针对东北 ALS 联盟诊所的临床计划。dALS 患者接受了C9orf72六核苷酸重复扩增 (HRE) 测试；患有 fALS 或 fALS/dALS 的患者接受了C9orf72 HRE 测试，然后对SOD1、FUS、TARDBP、TBK1和VCP进行测序。

结果

在 171/573 (30%) 的项目参与者中发现了致病 (P) 或可能致病 (LP) 变异。大约一半的 fALS 或 fALS/dALS 患者（138/301，45.8%）在SOD1、FUS、TARDBP、TBK1或VCP中发现了C9orf72 HRE 或 P 或 LP 变体。与其他基于临床的队列中使用的更大的面板相比，使用有针对性的 5 基因测序面板在家族病例中导致的不确定测试结果要少得多。在 dALS 病例中，11.8% (32/270) 被发现有C9orf72 HRE。非高加索地球血统的患者不太可能对C9orf72检测呈阳性HRE，但与高加索血统的人相比，更有可能在小组测试中呈阳性。