The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects

Cornelis Blauwendraat, Carlo Wilke, Javier Simón-Sánchez, Iris E Jansen, Anika Reifschneider, Anja Capell, Christian Haass, Melissa Castillo-Lizardo, Saskia Biskup, Walter Maetzler, Patrizia Rizzu, Peter Heutink, Matthis Synofzik

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

PurposeTo define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD).MethodsWe investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid Aβ1-42 and serum progranulin measurements. Subjects were screened for C9orf72 repeat expansions, GRN and MAPT mutations, and, if negative, mutations in other neurodegenerative disease genes, by whole-exome sequencing (WES) (n = 108), including WES-based copy-number variant (CNV) analysis.ResultsPathogenic and likely pathogenic mutations were identified in 19% of the subjects, including mutations in C9orf72 (n = 8), GRN (n = 7, one 11-exon macro-deletion) and, more rarely, CHCHD10, TARDBP, SQSTM1 and UBQLN2 (each n = 1), but not in MAPT or TBK1. WES also unraveled pathogenic mutations in genes not commonly linked to FTD, including mutations in Alzheimer (PSEN1, PSEN2), lysosomal (CTSF, 7-exon macro-deletion) and cholesterol homeostasis pathways (CYP27A1).ConclusionOur unbiased approach reveals a wide genetic spectrum underlying clinical FTD, including 11% of seemingly sporadic FTD. It unravels several mutations and CNVs in genes and pathways hitherto not linked to FTD. This suggests that clinical FTD might be the converging downstream result of a delicate susceptibility of frontotemporal brain networks to insults in various pathways.

Original languageEnglish
Pages (from-to)240-249
Number of pages10
JournalGenetics in Medicine
Volume20
Issue number2
DOIs
Publication statusPublished - Feb 2018

Cite this

Blauwendraat, Cornelis ; Wilke, Carlo ; Simón-Sánchez, Javier ; Jansen, Iris E ; Reifschneider, Anika ; Capell, Anja ; Haass, Christian ; Castillo-Lizardo, Melissa ; Biskup, Saskia ; Maetzler, Walter ; Rizzu, Patrizia ; Heutink, Peter ; Synofzik, Matthis. / The wide genetic landscape of clinical frontotemporal dementia : systematic combined sequencing of 121 consecutive subjects. In: Genetics in Medicine. 2018 ; Vol. 20, No. 2. pp. 240-249.
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title = "The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects",
abstract = "PurposeTo define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD).MethodsWe investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid Aβ1-42 and serum progranulin measurements. Subjects were screened for C9orf72 repeat expansions, GRN and MAPT mutations, and, if negative, mutations in other neurodegenerative disease genes, by whole-exome sequencing (WES) (n = 108), including WES-based copy-number variant (CNV) analysis.ResultsPathogenic and likely pathogenic mutations were identified in 19{\%} of the subjects, including mutations in C9orf72 (n = 8), GRN (n = 7, one 11-exon macro-deletion) and, more rarely, CHCHD10, TARDBP, SQSTM1 and UBQLN2 (each n = 1), but not in MAPT or TBK1. WES also unraveled pathogenic mutations in genes not commonly linked to FTD, including mutations in Alzheimer (PSEN1, PSEN2), lysosomal (CTSF, 7-exon macro-deletion) and cholesterol homeostasis pathways (CYP27A1).ConclusionOur unbiased approach reveals a wide genetic spectrum underlying clinical FTD, including 11{\%} of seemingly sporadic FTD. It unravels several mutations and CNVs in genes and pathways hitherto not linked to FTD. This suggests that clinical FTD might be the converging downstream result of a delicate susceptibility of frontotemporal brain networks to insults in various pathways.",
keywords = "Alleles, Biomarkers, C9orf72 Protein/genetics, Female, Frontotemporal Dementia/diagnosis, Gene Frequency, Genetic Association Studies/methods, Genetic Predisposition to Disease, Genetic Testing, Genotype, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Neurodegenerative Diseases/genetics, Pedigree, Phenotype, Sequence Analysis, DNA, Whole Exome Sequencing",
author = "Cornelis Blauwendraat and Carlo Wilke and Javier Sim{\'o}n-S{\'a}nchez and Jansen, {Iris E} and Anika Reifschneider and Anja Capell and Christian Haass and Melissa Castillo-Lizardo and Saskia Biskup and Walter Maetzler and Patrizia Rizzu and Peter Heutink and Matthis Synofzik",
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Blauwendraat, C, Wilke, C, Simón-Sánchez, J, Jansen, IE, Reifschneider, A, Capell, A, Haass, C, Castillo-Lizardo, M, Biskup, S, Maetzler, W, Rizzu, P, Heutink, P & Synofzik, M 2018, 'The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects' Genetics in Medicine, vol. 20, no. 2, pp. 240-249. https://doi.org/10.1038/gim.2017.102

The wide genetic landscape of clinical frontotemporal dementia : systematic combined sequencing of 121 consecutive subjects. / Blauwendraat, Cornelis; Wilke, Carlo; Simón-Sánchez, Javier; Jansen, Iris E; Reifschneider, Anika; Capell, Anja; Haass, Christian; Castillo-Lizardo, Melissa; Biskup, Saskia; Maetzler, Walter; Rizzu, Patrizia; Heutink, Peter; Synofzik, Matthis.

In: Genetics in Medicine, Vol. 20, No. 2, 02.2018, p. 240-249.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The wide genetic landscape of clinical frontotemporal dementia

T2 - systematic combined sequencing of 121 consecutive subjects

AU - Blauwendraat, Cornelis

AU - Wilke, Carlo

AU - Simón-Sánchez, Javier

AU - Jansen, Iris E

AU - Reifschneider, Anika

AU - Capell, Anja

AU - Haass, Christian

AU - Castillo-Lizardo, Melissa

AU - Biskup, Saskia

AU - Maetzler, Walter

AU - Rizzu, Patrizia

AU - Heutink, Peter

AU - Synofzik, Matthis

PY - 2018/2

Y1 - 2018/2

N2 - PurposeTo define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD).MethodsWe investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid Aβ1-42 and serum progranulin measurements. Subjects were screened for C9orf72 repeat expansions, GRN and MAPT mutations, and, if negative, mutations in other neurodegenerative disease genes, by whole-exome sequencing (WES) (n = 108), including WES-based copy-number variant (CNV) analysis.ResultsPathogenic and likely pathogenic mutations were identified in 19% of the subjects, including mutations in C9orf72 (n = 8), GRN (n = 7, one 11-exon macro-deletion) and, more rarely, CHCHD10, TARDBP, SQSTM1 and UBQLN2 (each n = 1), but not in MAPT or TBK1. WES also unraveled pathogenic mutations in genes not commonly linked to FTD, including mutations in Alzheimer (PSEN1, PSEN2), lysosomal (CTSF, 7-exon macro-deletion) and cholesterol homeostasis pathways (CYP27A1).ConclusionOur unbiased approach reveals a wide genetic spectrum underlying clinical FTD, including 11% of seemingly sporadic FTD. It unravels several mutations and CNVs in genes and pathways hitherto not linked to FTD. This suggests that clinical FTD might be the converging downstream result of a delicate susceptibility of frontotemporal brain networks to insults in various pathways.

AB - PurposeTo define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD).MethodsWe investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid Aβ1-42 and serum progranulin measurements. Subjects were screened for C9orf72 repeat expansions, GRN and MAPT mutations, and, if negative, mutations in other neurodegenerative disease genes, by whole-exome sequencing (WES) (n = 108), including WES-based copy-number variant (CNV) analysis.ResultsPathogenic and likely pathogenic mutations were identified in 19% of the subjects, including mutations in C9orf72 (n = 8), GRN (n = 7, one 11-exon macro-deletion) and, more rarely, CHCHD10, TARDBP, SQSTM1 and UBQLN2 (each n = 1), but not in MAPT or TBK1. WES also unraveled pathogenic mutations in genes not commonly linked to FTD, including mutations in Alzheimer (PSEN1, PSEN2), lysosomal (CTSF, 7-exon macro-deletion) and cholesterol homeostasis pathways (CYP27A1).ConclusionOur unbiased approach reveals a wide genetic spectrum underlying clinical FTD, including 11% of seemingly sporadic FTD. It unravels several mutations and CNVs in genes and pathways hitherto not linked to FTD. This suggests that clinical FTD might be the converging downstream result of a delicate susceptibility of frontotemporal brain networks to insults in various pathways.

KW - Alleles

KW - Biomarkers

KW - C9orf72 Protein/genetics

KW - Female

KW - Frontotemporal Dementia/diagnosis

KW - Gene Frequency

KW - Genetic Association Studies/methods

KW - Genetic Predisposition to Disease

KW - Genetic Testing

KW - Genotype

KW - Humans

KW - Magnetic Resonance Imaging

KW - Male

KW - Middle Aged

KW - Mutation

KW - Neurodegenerative Diseases/genetics

KW - Pedigree

KW - Phenotype

KW - Sequence Analysis, DNA

KW - Whole Exome Sequencing

U2 - 10.1038/gim.2017.102

DO - 10.1038/gim.2017.102

M3 - Article

VL - 20

SP - 240

EP - 249

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 2

ER -