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

Ramos EM1, Dokuru DR1, Van Berlo V1, Wojta K1, Wang Q1, Huang AY1, Deverasetty S1, Qin Y1, van Blitterswijk M2, Jackson J2, Appleby B3, Bordelon Y4, Brannelly P5, Brushaber DE6, Dickerson B7, Dickinson S8, Domoto-Reilly K9, Faber K10, Fields J6, Fong J11, Foroud T10, Forsberg LK6, Gavrilova R6, Ghoshal N12, Goldman J13, Graff-Radford J6, Graff-Radford N2, Grant I14, Grossman M15, Heuer HW11, Hsiung GR16, Huey E13, Irwin D15, Kantarci K6, Karydas A11, Kaufer D17, Kerwin D18, Knopman D6, Kornak J11, Kramer JH11, Kremers W6, Kukull W19, Litvan I20, Ljubenkov P11, Lungu C21, Mackenzie I16, Mendez MF4, Miller BL11, Onyike C22, Pantelyat A22, Pearlman R23, Petrucelli L2, Potter M10, Rankin KP11, Rascovsky K15, Roberson ED24, Rogalski E14, Shaw L15, Syrjanen J6, Tartaglia MC25, Tatton N8, Taylor J11, Toga A26, Trojanowski JQ15, Weintraub S14, Wong B7, Wszolek Z2, Rademakers R2, Boeve BF6, Rosen HJ11, Boxer AL11; ARTFL/LEFFTDS consortium, Coppola G1.

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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.