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

on behalf of the ARTFL/LEFFTDS consortium

doi:10.1002/alz.12011

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 journal › Article › peer-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 language	English (US)
Pages (from-to)	118-130
Number of pages	13
Journal	Alzheimer's and Dementia
Volume	16
Issue number	1
DOIs	https://doi.org/10.1002/alz.12011
State	Published - 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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10.1002/alz.12011

Cite this

@article{01bef3de546b42b59e248bb373641708,

title = "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",

author = "{on behalf of the ARTFL/LEFFTDS consortium} and Ramos, {Eliana Marisa} and Dokuru, {Deepika Reddy} and {Van Berlo}, Victoria and Kevin Wojta and Qing Wang and Huang, {Alden Y.} and Sandeep Deverasetty and Yue Qin and {van Blitterswijk}, Marka and Jazmyne Jackson and Brian Appleby and Yvette Bordelon and Patrick Brannelly and Brushaber, {Danielle E.} and Bradford Dickerson and Susan Dickinson and Kimiko Domoto-Reilly and Kelley Faber and Julie Fields and Jamie Fong and Tatiana Foroud and Forsberg, {Leah K.} and Ralitza Gavrilova and Nupur Ghoshal and Jill Goldman and Jonathan Graff-Radford and Neill Graff-Radford and Ian Grant and Murray Grossman and Heuer, {Hilary W.} and Hsiung, {Ging Yuek R.} and Edward Huey and David Irwin and Kejal Kantarci and Anna Karydas and Daniel Kaufer and Diana Kerwin and David Knopman and John Kornak and Kramer, {Joel H.} and Walter Kremers and Walter Kukull and Irene Litvan and Peter Ljubenkov and Codrin Lungu and Ian Mackenzie and Mendez, {Mario F.} and Miller, {Bruce L.} and Emily Rogalski and Sandra Weintraub",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2020 the Alzheimer's Association",

year = "2020",

month = jan,

day = "1",

doi = "10.1002/alz.12011",

language = "English (US)",

volume = "16",

pages = "118--130",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc.",

number = "1",

}

TY - JOUR

T1 - Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases

AU - on behalf of the ARTFL/LEFFTDS consortium

AU - Ramos, Eliana Marisa

AU - Dokuru, Deepika Reddy

AU - Van Berlo, Victoria

AU - Wojta, Kevin

AU - Wang, Qing

AU - Huang, Alden Y.

AU - Deverasetty, Sandeep

AU - Qin, Yue

AU - van Blitterswijk, Marka

AU - Jackson, Jazmyne

AU - Appleby, Brian

AU - Bordelon, Yvette

AU - Brannelly, Patrick

AU - Brushaber, Danielle E.

AU - Dickerson, Bradford

AU - Dickinson, Susan

AU - Domoto-Reilly, Kimiko

AU - Faber, Kelley

AU - Fields, Julie

AU - Fong, Jamie

AU - Foroud, Tatiana

AU - Forsberg, Leah K.

AU - Gavrilova, Ralitza

AU - Ghoshal, Nupur

AU - Goldman, Jill

AU - Graff-Radford, Jonathan

AU - Graff-Radford, Neill

AU - Grant, Ian

AU - Grossman, Murray

AU - Heuer, Hilary W.

AU - Hsiung, Ging Yuek R.

AU - Huey, Edward

AU - Irwin, David

AU - Kantarci, Kejal

AU - Karydas, Anna

AU - Kaufer, Daniel

AU - Kerwin, Diana

AU - Knopman, David

AU - Kornak, John

AU - Kramer, Joel H.

AU - Kremers, Walter

AU - Kukull, Walter

AU - Litvan, Irene

AU - Ljubenkov, Peter

AU - Lungu, Codrin

AU - Mackenzie, Ian

AU - Mendez, Mario F.

AU - Miller, Bruce L.

AU - Rogalski, Emily

AU - Weintraub, Sandra

N1 - Funding Information: 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. Publisher Copyright: © 2020 the Alzheimer's Association

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - C9orf72

KW - GRN

KW - MAPT

KW - familial

KW - frontotemporal dementia

KW - sporadic

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U2 - 10.1002/alz.12011

DO - 10.1002/alz.12011

M3 - Article

C2 - 31914217

AN - SCOPUS:85077731767

SN - 1552-5260

VL - 16

SP - 118

EP - 130

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 1

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

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