Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement

doi:10.1016/j.neurobiolaging.2018.04.003

Neurobiology of Aging

Volume 68, August 2018, Pages 160.e15-160.e19

https://doi.org/10.1016/j.neurobiolaging.2018.04.003 Get rights and content

Abstract

To identify genes associated with frontotemporal dementia (FTD) in South-East Asia, targeted exome sequencing and C9orf72 genotyping was performed in 198 subjects (52 patients with FTD and 146 healthy controls) who were screened for mutations in 12 FTD-associated genes. We detected a homozygous TREM2 R47C mutation in a patient with behavioral variant FTD without bone cysts or bone-associated phenotype. Two novel nonsense GRN mutations in 3 FTD patients from the Philippines were detected, but no known pathogenic mutations in other FTD-associated genes were found. In 45 subjects screened for C9orf72 repeat expansions, no pathogenic expansion (≥30 repeats) was identified, but there was a higher proportion of intermediate length (≥10–29 repeats) alleles in patients compared with controls (8/90 alleles, 8.9% vs. 9/164 alleles, 5.5%). Overall, we detected a mutation rate of 7.7% (4/52 patients) in our cohort. Given recent findings of enrichment of rare TREM2 variants (including R47C) in Alzheimer's disease, it is notable that we detected a homozygous TREM2 R47C carrier presenting with an FTD rather than an Alzheimer's disease phenotype.

Introduction

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by behavioral and/or language impairment (Rascovsky et al., 2011). Genes associated with familial FTD (fFTD) include microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP), coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), TAR DNA-binding protein (TARDBP), fused-in sarcoma (FUS), optineurin (OPTN), TANK binding-kinase 1 (TBK1), sequestosome-1 (SQSTM1), charged multivesicular body protein 2B (CHMP2B), and chromosome 9 open-reading frame 72 (C9orf72). Of these, MAPT and GRN mutations and C9orf72 hexanucleotide repeat expansions are the most common and account for about nearly half of fFTD cases (Seelaar et al., 2011). These genes were included in a targeted exome-sequencing panel of 200 neurodegenerative disease-related genes to identify disease mutations in a South-East Asian cohort of patients with FTD spectrum disorders.

Section snippets

Patient recruitment

Between January 2015 and November 2016, patients were prospectively recruited from the behavioral neurology clinics at the National Neuroscience Institute, Singapore. Eight patients were recruited from the Institute of Neurological Sciences, St Luke's Medical Centre in the Philippines. All patients enrolled met research criteria for bvFTD (behavioral variant frontotemporal dementia) (Rascovsky et al., 2011), semantic variant primary progressive aphasia (PPA) (Gorno-Tempini et al., 2011),

Genetic analysis

A total of 52 patients with FTD spectrum disorders (mean age 62.0 ± 7.7 years) were included. Their demographics are summarized in Supplementary Table A.3. A total of 12 FTD-related genes were screened: MAPT, GRN, C9orf72, FUS, VCP, SQSTM1, TBK1, OPTN, TARDBP, CHCHD10, CHMP2B, and TREM2. Sequencing of MAPT, FUS, VCP, SQSTM1, TBK1, OPTN, TARDBP, CHCHD10, and CHMP2B genes identified no known pathogenic variant. Five nonsynonymous variants of unknown significance detected in MAPT, GRN, CHMP2B,

Two novel GRN mutations in 3 patients with bvFTD and nfvPPA from the Philippines

The GRN gene is located on chromosome 17, 1.7 Mb upstream of MAPT, and has 12 coding exons encoding progranulin (Cruts et al., 2006). Progranulin has roles in cell-cell signaling and signal transduction and is implicated in cell proliferation, wound repair, and as a growth factor (He and Bateman, 1999). Pathogenic GRN mutations have been reported predominantly in FTD and not in other neurodegenerative diseases, with haploinsufficiency as the predominant mechanism leading to disease (Yu et al.,

Conclusion

In summary, this is the first report of South-East Asian FTD patients screened for mutations in both common and rarer FTD-associated genes. We detected 2 novel GRN mutations in 3 subjects from the Philippines, as well as a homozygous TREM2 p.Arg47Cys (R47 C) carrier of South Asian ancestry who presented with bvFTD in her late-50s. To our knowledge, this is the first report of a homozygous TREM2 p.Arg47Cys carrier. Our patient presented in mid-life with classical bvFTD rather than AD, contrary

Disclosure statement

The authors have no actual or potential conflicts of interest.

Acknowledgements

Funding: This work was supported by Singapore's National Medical Research Council (grant numbers NMRC/CNIG/1165/2017, NMRC/CIRG/1416/2015) and the National Research Foundation of Singapore (grant number NRF-NRFF2016-03).

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Mutations in either TREM2 or TYROBP are known to cause PLOSL. More recently, in some studies, homozygous or compound heterozygous mutations in TREM2 were found associated with early-onset dementia with or without bone involvement (Chee et al., 2017; Chouery et al., 2008; Ghezzi et al., 2017; Giraldo et al., 2013; Guerreiro et al., 2013a,b; Le Ber et al., 2014; Ng, 2018). Herein, we report a novel homozygous mutation in TREM2, which was associated with early-onset dementia with very mild bone involvement in a Chinese Han family.
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Alzheimer's disease is a genetically complex disorder; rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene have been shown to as much as triple an individual's risk of developing Alzheimer's disease. TREM2 is a transmembrane receptor expressed in cells of the myeloid lineage, and its association with Alzheimer's disease supports the involvement of immune and inflammatory pathways in the cause of the disease, rather than as a consequence of the disease. TREM2 variants associated with Alzheimer's disease induce partial loss of function of the TREM2 protein and alter the behaviour of microglial cells, including their response to amyloid plaques. TREM2 variants have also been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy and frontotemporal dementia. Although the low frequency of TREM2 variants makes it difficult to establish robust genotype–phenotype correlations, such studies are essential to enable a comprehensive understanding of the role of TREM2 in different neurological diseases, with the ultimate goal of developing novel therapeutic approaches.
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Genetic reports abstractTargeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement

Abstract

Introduction

Section snippets

Patient recruitment

Genetic analysis

Two novel GRN mutations in 3 patients with bvFTD and nfvPPA from the Philippines

Conclusion

Disclosure statement

Acknowledgements

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Parkinsonism Relat. Disord.

Neurobiol. Aging

Parkinsonism Relat. Disord

A method and server for predicting damaging missense mutations

Nat. Methods

Criteria for the diagnosis of corticobasal degeneration

Neurology

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Nature

TREMs in the immune system and beyond

Nat. Rev. Immunol.

Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21

Nature

Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members

Brain

Genetic reports abstract
Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement