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

• Published in: Genetics in medicine Vol. 20; no. 2; pp. 240 - 249
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2018; Elsevier Limited; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/514; 631/208/726/649; 692/617/375/132; Alleles; Biomarkers; Biomedical and Life Sciences; Biomedicine; C9orf72 Protein - genetics; Dementia; Female; Frontotemporal Dementia - diagnosis; Frontotemporal Dementia - epidemiology; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Gene Frequency; Genetic Association Studies - methods; Genetic Predisposition to Disease; Genetic Testing; Genotype; Human Genetics; Humans; Laboratory Medicine; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Neurodegenerative Diseases - genetics; Original; original-research-article; Pedigree; Phenotype; Sequence Analysis, DNA; Whole Exome Sequencing; frontotemporal dementia; neuronal ceroid lipofuscinosis; Alzheimer disease; cerebrotendinous xanthomatosis; whole-exome sequencing
• DOI: 10.1038/gim.2017.102
• ISSN: 1098-3600; 1530-0366

Purpose To define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD). Methods We investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid Aβ 1-42 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. Results Pathogenic 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 ). Conclusion Our 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.