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Alzheimers Dement. 2020 Jan;16(1):118-130. doi: 10.1002/alz.12011.

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

Author information

1
Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
2
Mayo Clinic, Jacksonville, Florida.
3
Case Western Reserve University, Cleveland, Ohio.
4
University of California Los Angeles, Los Angeles, California.
5
Tau Consortium, Rainwater Charitable Foundation, Fort Worth, Texas.
6
Mayo Clinic, Rochester, Minnesota.
7
Harvard University/MGH, Boston, Massachusetts.
8
Association for Frontotemporal Degeneration, Radnor, Pennsylvania.
9
University of Washington, Seattle, Washington.
10
National Centralized Repository for Alzheimer's Disease and Related Dementia (NCRAD), Indiana University, Indianapolis, Indiana.
11
University of California, San Francisco, San Francisco, California.
12
Washington University, St. Louis, Missouri.
13
Columbia University, New York, New York.
14
Northwestern University, Chicago, Illinois.
15
University of Pennsylvania, Philadelphia, Pennsylvania.
16
University of British Columbia, Vancouver, British Columbia, Canada.
17
University of North Carolina, Chapel Hill, North Carolina.
18
University of Texas Southwestern Medical Center, Dallas, Texas.
19
National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, Washington.
20
University of California, San Diego, San Diego, California.
21
National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland.
22
Johns Hopkins University, Baltimore, Maryland.
23
Bluefield Project, San Francisco, California.
24
University of Alabama at Birmingham, Birmingham, Alabama.
25
University of Toronto, Toronto, Ontario, Canada.
26
Laboratory of Neuroimaging (LONI), USC, Los Angeles, California.

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

PMID:
31914217
DOI:
10.1002/alz.12011

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