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

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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.

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Acknowledgements

We are grateful to the patients and their families and to Miss Cecilia Baroncini for English editing and to Professor Kevin Talbot for his opinions on the manuscript. The authors gratefully acknowledge the Italian Ministry of Research RFO, Fondazione del Monte, Fondazione Gino Galletti for funding support.

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Authors and Affiliations

  1. UOC Clinica Neurologica, Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy

    Maria Pia Giannoccaro, Anna Bartoletti-Stella, Simone Baiardi, Patrizia Avoni, Piero Parchi, Rocco Liguori & Sabina Capellari

  2. Dipartimento Neuroscienze, psicologia, area del farmaco e salute del bambino, Università di Firenze, Firenze, Italy

    Anna Bartoletti-Stella

  3. IRCCS Istituto delle Scienze Neurologiche, UOC Clinica Neurologica, Ospedale Bellaria, via Altura, 3, Bologna, Italy

    Silvia Piras, Federico Oppi, Michelangelo Stanzani-Maserati, Elena Pasini, Patrizia Avoni, Piero Parchi, Rocco Liguori & Sabina Capellari

  4. UOC Anatomia patologica, Dipartimento di Scienze Oncologiche, via Altura, 3, 40136, Bologna, Italy

    Annalisa Pession

  5. SSD Neurologia, AUSL di Imola, Via Montericco, 4, 40026, Imola, Italy

    Patrizia De Massis

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  1. Maria Pia Giannoccaro
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Correspondence to Maria Pia Giannoccaro or Sabina Capellari.

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Italian Ministry of Research RFO, Fondazione del Monte, Fondazione Gino Galletti to SC, PP, RL and AIRAlzh Onlus-COOP Italia to ABS.

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Giannoccaro, M.P., Bartoletti-Stella, A., Piras, S. et al. Multiple variants in families with amyotrophic lateral sclerosis and frontotemporal dementia related to C9orf72 repeat expansion: further observations on their oligogenic nature. J Neurol 264, 1426–1433 (2017). https://doi.org/10.1007/s00415-017-8540-x

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