Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the <i>C9orf72</i> expansion mutation.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. 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 (<i>C9orf72</i>) hexanucleotide repeat expansion, the most important genetic cause in both diseases. 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 <i>C9orf72</i>. 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. We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. <i>TBK1</i> was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was <i>SQSTM1</i>, with three mutation carriers (one of them also harboured a <i>TBK1</i> mutation). We also detected probable pathogenic genetic alterations in <i>TAF15</i>, <i>VCP</i> and <i>TARDBP</i> and possible pathogenic mutations in <i>FIG4</i> and <i>ERBB4</i>. Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with <i>TAF15</i>, <i>FIG4</i> and <i>ERBB4</i> to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the <i>C9orf72</i> expansion mutation, regardless of family history of disease.