Effect of familial clustering in the genetic screening of 235 French ALS families
- 6 January 2021
- journal article
- research article
- Published by BMJ in Journal of Neurology, Neurosurgery & Psychiatry
- Vol. 92 (5), 479-484
- https://doi.org/10.1136/jnnp-2020-325064
Abstract
Objectives To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved. Methods We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed. Results Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years. Conclusion Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.Keywords
This publication has 30 references indexed in Scilit:
- Causative Genes in Amyotrophic Lateral Sclerosis and Protein Degradation Pathways: a Link to NeurodegenerationMolecular Neurobiology, 2018
- Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implicationsThe Lancet Neurology, 2017
- Amyotrophic Lateral SclerosisThe New England Journal of Medicine, 2017
- Amyotrophic lateral sclerosisThe Lancet, 2017
- Familial clustering of ALS in a population-based resourceNeurology, 2014
- State of play in amyotrophic lateral sclerosis geneticsNature Neuroscience, 2013
- Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutationsNeurology, 2012
- Phenotype difference between ALS patients with expanded repeats inC9ORF72and patients with mutations in other ALS-related genesJournal of Medical Genetics, 2012
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993
- Epidemiologic Investigations of Amyotrophic Lateral SclerosisNeurology, 1955