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Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement
Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B et al.. JAMA neurology, 2013-01-01
Topic: Brain proteins, microglia and lab models
Objective To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. Design Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. Setting Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. PATIENTS Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. Main outcome measure Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). Results In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. Conclusions Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.
Key findings
- Objective To identify new genes and risk factors associated with frontotemporal dementia (FTD).
- Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes.
- Results In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL).
- Conclusions Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded.
Why it matters
Among 44 Turkish patients with a frontotemporal dementia-like illness seen at one Istanbul clinic, gene sequencing found that 3 carried two altered copies of TREM2, a gene previously tied to the bone-and-brain disorder PLOSL. None of the 3 had bone cysts: they "presented with behavioral change and subsequent cognitive impairment and motor features", and brain scans showed white matter changes and frontal shrinkage. The authors suggest TREM2 "should be taken into account when mutations in other dementia genes are excluded"; this is a small single-clinic case series, not a treatment study, and its carrier rate may not apply elsewhere.
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Study details
- Evidence strengthModerate
How this study scored 57/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (JAMA neurology) |
| Journal's citation record | 2 / 4 | JAMA Neurology: journal h-index 235 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2013 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 377 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 25.1 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 5 / 6 | Cited 24.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 86 other studies in this library |
| Still being cited | 3 / 4 | Cited 61 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author John Hardy: h-index 205 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | National Institutes of Health: institution h-index 2,723 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 23318515) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 57 / 100 | — |
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Read the original
- DOI: 10.1001/jamaneurol.2013.579
- PubMed: 23318515
- Original source →
- Free full text: PubMed Central →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, JR., Rohrer, J. D., Gurunlian, N., et al. (2013). Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA neurology. https://doi.org/10.1001/jamaneurol.2013.579
Vancouver
Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA neurology. 2013. doi:10.1001/jamaneurol.2013.579. PMID: 23318515.
BibTeX
@article{guerreiro2013-23318515,
author = {Guerreiro, R. J. and Lohmann, E. and Brás, J. M. and Gibbs, JR. and Rohrer, J. D. and Gurunlian, N. and Dursun, B. and Bilgic, B. and others},
title = {{Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement}},
journal = {JAMA neurology},
year = {2013},
doi = {10.1001/jamaneurol.2013.579},
pmid = {23318515},
url = {https://doi.org/10.1001/jamaneurol.2013.579}
}
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