RT Journal Article SR Electronic T1 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 JF Journal of Neurology, Neurosurgery & Psychiatry JO J Neurol Neurosurg Psychiatry FD BMJ Publishing Group Ltd SP jnnp-2017-316820 DO 10.1136/jnnp-2017-316820 A1 Oriol Dols-Icardo A1 Alberto García-Redondo A1 Ricardo Rojas-García A1 Daniel Borrego-Hernández A1 Ignacio Illán-Gala A1 José Luís Muñoz-Blanco A1 Alberto Rábano A1 Laura Cervera-Carles A1 Alexandra Juárez-Rufián A1 Nino Spataro A1 Noemí De Luna A1 Lucía Galán A1 Elena Cortes-Vicente A1 Juan Fortea A1 Rafael Blesa A1 Oriol Grau-Rivera A1 Alberto Lleó A1 Jesús Esteban-Pérez A1 Ellen Gelpi A1 Jordi Clarimón YR 2017 UL http://jnnp.bmj.com/content/early/2017/09/09/jnnp-2017-316820.abstract AB 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.