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We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree. Most patients (74.4%) were diagnosed with frontotemporal dementia, while others had a clinical diagnosis of unspecified dementia, Alzheimer's dementia or Parkinson's disease. The observed clinical heterogeneity can guide clinical diagnosis, genetic testing, and counseling of mutation carriers. Onset of initial symptomatology is highly variable, ranging from age 45 to 80 years. Analysis of known modifiers, suggested effects of GRN rs5848, microtubule-associated protein tau H-1/H-2, and chromosome 9 open reading frame 72 G(4)C(2) repeat length on onset age but explained only a minor fraction of the variability. Contrary, the extended GRN founder family is a valuable source for identifying other onset age modifiers based on exome or genome sequences. These modifiers might be interesting targets for developing disease-modifying therapies. (C) 2018 The Authors. Published by Elsevier Inc. ; Belgian Science Policy Office Interuniversity Attraction Poles program; Flemish government initiated Methusalem excellence program; Flemish government initiated Impulse Program on Networks for Dementia Research; Queen Elisabeth Medical Foundation; Alzheimer Research Foundation; Research Foundation Flanders (FWO); Agency for Innovation by Science and Technology Flanders (IWT); University of Antwerp Research Fund; Belgium; IWT; FWO

© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) ; We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD. ; The research was funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program; the Flemish government initiated Methusalem excellence program and Impulse Program on Networks for Dementia Research; the Research Foundation Flanders (FWO), the Agency for Innovation by Science and Technology Flanders (IWT) and the University of Antwerp Research Fund; Belgium. SP received a PhD fellowship of the FWO and EW of the IWT. RG, LB, and GB (IRCCS Fatebenefratelli, Brescia, Italy) were supported by Ricerca Corrente, Italian Ministry of Health. ; info:eu-repo/semantics/publishedVersion