Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases

Abstract

Introduction: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.

Methods: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies.

Results: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.

Discussion: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

Keywords: C9orf72; GRN; MAPT; familial; frontotemporal dementia; sporadic.

© 2020 the Alzheimer's Association.

Figures

FIGURE 1

Clinical and genetic characteristics of individuals enrolled in the ARTFL/LEFFTDS studies. (a) Clinical diagnoses among 346 sporadic patients with dementia (left) and 390 individuals with a family history of FTD (right). (b) Carriers of (likely) pathogenic variants in the main FTD genes (red) among 302 sporadic cases diagnosed with FTD-spectrum phenotypes (blue, left), and in 390 individuals with family history of FTD (green, right). One individual carried both an expanded C9orf72 repeat and a known pathogenic GRN variant. (AD, Alzheimer’s disease dementia; ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant FTD; CBS, corticobasal syndrome; FTD, frontotemporal dementia; lvPPA, logopenic variant PPA; MCI, mild cognitive impairment; nfvPPA, non-fluent variant PPA; PPA, primary progressive aphasia; PSP, progressive supranuclear palsy; svPPA, semantic variant PPA)

FIGURE 2

Schematic representation of GRN and MAPT variants found in the ARTFL/LEFFTDS series. Pathogenic variants (red) are represented in the topologic protein models of (a) tau (Uniprot accession P10636–9) and (b) progranulin (Uniprot accession P28799). (a) The canonical MAPT transcript (GenBank accession NM_001123066) contains 15 exons (including non-coding exon 1), with exons 6, 8, and 10 (white) not expressed in human brain, whereas exons 3, 4, and 12 (yellow) are alternatively spliced and adult brain-specific. The tubulin-binding region (blue) in the C-terminal can include either three (R1, R3, and R4) or four (R1, R2, R3, and R4) repeat regions, with the fourth microtubule-binding domain being encoded by the alternatively spliced exon 10 (bottom panel). Together, these give rise to six different possible tau isoforms in the human brain. Historical names for the MAPT mutations are shown in brackets. (b) Progranulin, encoded by the GRN gene (GenBank accession NM_002087), is a secreted precursor protein comprising a signal peptide (SP, dark gray), paragranulin (GrnP), and granulins (Grn) A to G. Cleavage of the signal peptide produces mature granulin, which can undergo further proteolytic cleavage resulting in a variety of active granulins

FIGURE 3

Clinical presentation among C9orf72, MAPT, and GRN mutation carriers. Although the majority of carriers were asymptomatic at baseline assessment, bvFTD was the most common phenotypic presentation among C9orf72 and MAPT mutation carriers, whereas the clinical spectrum was more heterogeneous among GRN carriers. Numbers of individuals with gene mutations are listed under each diagnostic category. (AD, Alzheimer’s disease dementia; ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia (FTD); CBS, corticobasal syndrome; lvPPA, logopenic variant PPA; MCI, mild cognitive impairment; nfvPPA, non-fluent variant PPA; PPA, primary progressive aphasia; svPPA, semantic variant PPA)