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Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation
  1. Oriol Dols-Icardo1,2,
  2. Alberto García-Redondo3,4,
  3. Ricardo Rojas-García4,5,
  4. Daniel Borrego-Hernández3,
  5. Ignacio Illán-Gala1,2,
  6. José Luís Muñoz-Blanco6,
  7. Alberto Rábano7,
  8. Laura Cervera-Carles1,2,
  9. Alexandra Juárez-Rufián3,4,
  10. Nino Spataro8,9,
  11. Noemí De Luna4,5,
  12. Lucía Galán10,
  13. Elena Cortes-Vicente5,
  14. Juan Fortea1,2,
  15. Rafael Blesa1,2,
  16. Oriol Grau-Rivera11,12,
  17. Alberto Lleó1,2,
  18. Jesús Esteban-Pérez3,4,
  19. Ellen Gelpi11,
  20. Jordi Clarimón1,2
  1. 1Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
  2. 2Center for Networked Biomedical Research into Neurodegenerative Diseases (CIBERNED), Madrid, Spain
  3. 3ALS Unit, Department of Neurology, Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain
  4. 4Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
  5. 5Neuromuscular Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
  6. 6ALS Unit, Department of Neurology, Hospital Universitario Gregorio Marañón, Madrid, Spain
  7. 7Department of Neuropathology and Tissue Bank, CIEN Foundation, Carlos III Institute of Health, Madrid, Spain
  8. 8Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
  9. 9Universitat Pompeu Fabra (UPF), Barcelona, Spain
  10. 10ALS Unit, Department of Neurology, Hospital Clínico Universitario San Carlos, Madrid, Spain
  11. 11Neurological Tissue Bank of the Biobanc-Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  12. 12Alzheimer’s Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, Barcelona, Spain
  1. Correspondence to Dr Jordi Clarimón, Department of Neurology, Research Institute. HSCSP, C/Sant Antoni Maria Claret, 167, Barcelona 08025, Spain; jclarimon{at}


Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum.

Objectives The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases.

Methods From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes.

Results We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4.

Conclusion Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.

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  • Contributors ODI, AGR, RRG, OGR, EG and JC processed and interpreted the data, wrote and revised the manuscript and designed the study. DBH, IIG, JLMB, AR, LCC, AJR, NS, NDL, LG, ECV, JF, RB, AL and JEP interpreted the data and revised the manuscript.

  • Funding Funding for the project was provided by the Spanish Ministry of Economy and Competitiveness, projects I+D+i 2008, Subprograma de actuaciones Científicas y Tecnológicas en Parques Científicos y Tecnológicos (ACTEPARQ 2009) and ERFD. ODI is funded by Departament de Salut de la Generalitat de Catalunya, Pla estratègic de recerca i innovació en salut (PERIS) 2016-2020 (SLT002/16/00040). PI15/00026 to JC and PI13/00772 and PI15/01618 to RRG jointly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, ‘Una manera de hacer Europa’. Telemaratón de RTVE ‘Todos somos raros, todos somos únicos’ (Project num. 29) also funded this study. This work was also supported in part by Generalitat de Catalunya (2014SGR-0235) and Fundació La Marató de TV3 under Grant 201437.10. IIG is supported by i-PFIS grant (IF15/00060) from Instituto de Salud Carlos III. National Registry of Motor Neuron Disease (NMD-ES Project) is partially funded by Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). This study makes use of data generated by the Medical Genome Project. A full list of the investigators who contributed to the generation of the data is available from

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.