Multiple variants in families with amyotrophic lateral sclerosis and frontotemporal dementia related to C9orf72 repeat expansion: further observations on their oligogenic nature

Maria Pia Giannoccaro, Anna Bartoletti-Stella, Silvia Piras, Annalisa Pession, Patrizia De Massis, Federico Oppi, Michelangelo Stanzani-Maserati, Elena Pasini, Simone Baiardi, Patrizia Avoni, Piero Parchi, Rocco Liguori, Sabina Capellari

Research output: Contribution to journalArticlepeer-review

Abstract

The C9orf72 repeat expansion (RE) is one of the most frequent causative mutations of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is still unclear how the C9orf72 RE can lead to a heterogeneous phenotype. Several reports have shown the coexistence of mutations in multiple ALS/FTD causative genes in the same family, suggesting an oligogenic etiology for ALS and FTD. Our aim was to investigate this phenomenon in an Italian group of ALS/FTD pedigrees carrying the C9orf72 RE. We included 11 subjects from 11 pedigrees with ALS/FTD and the C9orf72 RE. Mutation screening of FUS, SOD1 and TARDBP genes was performed by direct sequencing. A dementia-specific custom-designed targeted next-generation sequencing panel was used for screening dementia-associated genes mutations. We found genetic variants in additional ALS or dementia-related genes in four pedigrees, including the p.V47A variant in the TYROBP gene. As a group, double mutation carriers displayed a tendency toward a younger age at onset and a higher frequency of positive familiar history and of parkinsonism. Our observation supports the hypothesis that the co-presence of mutations in different genes may be relevant for the clinical expression of ALS/FTD and of their oligogenic nature.

Original languageEnglish
Pages (from-to)1426-1433
Number of pages8
JournalJournal of Neurology
Volume264
Issue number7
DOIs
Publication statusPublished - Jul 1 2017

Keywords

  • ALS
  • C9orf72 repeat expansion
  • FTD
  • Oligogenic
  • TYROBP

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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