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 http://www.medicalgenomeproject.com/en.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.