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

on behalf of the ARTFL/LEFFTDS consortium

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)118-130
Number of pages13
JournalAlzheimer's and Dementia
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2020

Funding

Samples from the National Centralized Repository for Alzheimer's Disease and Related Dementia (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. We thank the UCLA Neuroscience Genomics Core (www.semel.ucla.edu/ungc) for assistance with sequencing data generation and the support of the National Institute of Neurological Disorders and Stroke (NINDS) Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691). We also thank the MacArthur lab at the Broad Institute for assistance in implementing the ARTFL/LEFFTDS browser, generated using their ExAC database interface. We extend our appreciation to Dr. John Hsiao from NIA and Dr. Margaret Sutherland from NINDS.

Keywords

  • C9orf72
  • GRN
  • MAPT
  • familial
  • frontotemporal dementia
  • sporadic

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Health Policy
  • Developmental Neuroscience
  • Epidemiology

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