Targeted sequencing panels in Italian ALS patients support different etiologies in the ALS/FTD continuum.

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5-10% of amyotrophic lateral sclerosis (ALS) patients presented a positive family history (fALS). More than 30 genes have been identified in association with ALS/frontotemporal dementia (FTD) spectrum, with four major genes accounting for 60-70% of fALS. In this paper, we aimed to assess the contribution to the pathogenesis of major and rare ALS/FTD genes in ALS patients.We analyzed ALS and ALS/FTD associated genes by direct sequencing or next-generation sequencing multigene panels in ALS patients.Genetic abnormalities in ALS major genes included repeated expansions of hexanucleotide in C9orf72 gene (7.3%), mutations in SOD1 (4.9%), FUS (2.1%), and TARDBP (2.4%), whereas variants in rare ALS/FTD genes affected 15.5% of subjects overall, most frequently involving SQSTM1 (3.4%), and CHMP2B (1.9%). We found clustering of variants in ALS major genes in patients with a family history for "pure" ALS, while ALS/FTD related genes mainly occurred in patients with a family history for other neurodegenerative diseases (dementia and/or parkinsonism).Our data support the presence of two different genetic components underlying ALS pathogenesis, related to the presence of a family history for ALS or other neurodegenerative diseases. Thus, family history may help in optimizing the genetic screening protocol to be applied.


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Authors: Anna Bartoletti-Stella, Veria Vacchiano, Silvia De Pasqua, Giacomo Mengozzi, Dario De Biase, Ilaria Bartolomei, Patrizia Avoni, Giovanni Rizzo, Piero Parchi, Vincenzo Donadio, Adriano Chiò, Annalisa Pession, Federico Oppi, Fabrizio Salvi, Rocco Liguori, Sabina Capellari, BoReALS

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