title: Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement.
abstract: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. r.guerreiro@ucl.ac.uk
authors: Rita João
authors: RJ
authors: Guerreiro
authors: Ebba
authors: E
authors: Lohmann
authors: José Miguel
authors: JM
authors: Brás
authors: Jesse Raphael
authors: JR
authors: Gibbs
authors: Jonathan D
authors: JD
authors: Rohrer
authors: Nicole
authors: N
authors: Gurunlian
authors: Burcu
authors: B
authors: Dursun
authors: Basar
authors: B
authors: Bilgic
authors: Hasmet
authors: H
authors: Hanagasi
authors: Hakan
authors: H
authors: Gurvit
authors: Murat
authors: M
authors: Emre
authors: Andrew
authors: A
authors: Singleton
authors: John
authors: J
authors: Hardy
mesh_terms: D000328:Adult; D059472:Exome / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors; D013577:Syndrome
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human