Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis

• DOI: 10.1093/braincomms/fcad152
• Publication Date: 2023-05-11T00:43:47Z
• Authors: Wolfgang P Ruf; Matej Boros; Axel Freischmidt; David Brenner; Veselin Grozdanov; Joao de Meirelles; Thomas Meyer; Torsten Grehl; Susanne Petri; Julian Grosskreutz; Ute Weyen; Rene Guenther; Martin Regensburger; Tim Hagenacker; Jan C Koch; Alexander Emmer; Annekathrin Roediger; Robert Steinbach; Joachim Wolf; Jochen H Weishaupt; Paul Lingor; Marcus Deschauer; Isabell Cordts; Thomas Klopstock; Peter Reilich; Florian Schoeberl; Berthold Schrank; Daniel Zeller; Andreas Hermann; Antje Knehr; Kornelia Günther; Johannes Dorst; Joachim Schuster; Reiner Siebert; Albert C Ludolph; Kathrin Müller
• Keywords: C9ORF72

Therapy of motoneuron diseases entered a new phase with the use intrathecal antisense oligonucleotide therapies treating patients specific gene mutations predominantly in context familial amyotrophic lateral sclerosis. With majority cases being sporadic, we conducted cohort study to describe mutational landscape sporadic We analysed genetic variants sclerosis-associated genes assess and potentially increase number eligible for gene-specific therapies. screened 2340 sclerosis from German Network motor neuron 36 using targeted next-generation sequencing C9orf72 hexanucleotide repeat expansion. The analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate survival. In this study, found 79 likely pathogenic Class 4 10 5 (without expansion) according American College Medical Genetics Genomics guidelines, which 31 are novel. Thus, including expansion, 4, variants, 296 patients, corresponding ∼13% our cohort, genetically resolved. detected 437 unknown significance 103 Corroborating theory oligogenic causation sclerosis, co-occurrence (0.4%) 7 expansion carriers. gene-wise survival analysis, higher hazard ratio 1.47 (95% confidence interval 1.02-2.1) death any cause lower 0.33 0.12-0.9) SOD1 than without causal mutation. summary, high yield (∼13%) harbouring variant oncoming SOD1/FUS/C9orf72, would apply 227 (∼10%) corroborates that testing should made available all after respective counselling.