Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with theC9orf72 repeat expansion being the most common genetic cause. While the prevalence ofC9orf72-ALS in patients from different populations has been studied, data regarding the yield ofC9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application ofC9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018 –2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (<  50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for theC9orf72 repeat expansion and 64 (54%) underwent gene panel testing. TheC9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% forC9orf72.We suggest a testing strategy for the Israeli ALS patients:C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including...
Source: Journal of Neurology - Category: Neurology Source Type: research