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.

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.

Figure 1

Pedigrees of the 3 families where triggering receptor expressed on myeloid cells 2 gene (TREM2) mutations were found. Arrowheads indicate probands. Black filled symbols represent affected subjects with dementia. White symbols represent unaffected family members and white symbols with a black dot represent individuals where dementia has been reported but not clinically confirmed. The genotypes (N indicates normal and M, mutation found) are represented for those individuals for whom DNA samples were available.

Figure 2

Magnetic resonance images from the proband of family 1. Sagittal T1-weighted (A), axial T2-weighted (B), and coronal T1-weighted (C) images show marked thinning of the corpus callosum; diffuse confluent white matter abnormalities in the periventricular white matter, especially adjacent to the anterior and posterior horns of the lateral ventricle; cortical atrophy; and disproportionally enlarged ventricles.

Figure 3

Magnetic resonance images from the proband of family 2. Sagittal T2-weighted (A), coronal T1-weighted (B), and axial fluid-attenuated inversion recovery–weighted (C) images show thinning of the corpus callosum with cortical atrophy and periventricular white matter abnormalities.

Figure 4

Magnetic resonance images from the proband of family 3. Sagittal T1-weighted (A), axial fluid-attenuated inversion recovery–weighted (B), and coronal T2-weighted (C) images reveal significant thinning of the corpus callosum; diffuse confluent white matter abnormalities in the periventricular white matter, especially adjacent to the anterior and posterior horns of the lateral ventricle; global cortical atrophy; and enlarged ventricles.

Figure 5

The triggering receptor expressed on myeloid cells 2 gene (TREM2) structure spans 41126246 to 41130922 base pairs (bp) on chromosome (chr) 6p21.1. A, Schematic of TREM2 (drawn using FancyGene19), the mutation nomenclature given with respect to RefSeq identifier NM_018965.2. Exons are drawn to scale and represented with gray boxes with untranslated regions (UTR) in red. Mutation locations are approximate: mutations identified in this study are represented below and previously described mutations are represented on top. B, The conservation of mutations identified in the present study. GenBank accession numbers: NP_061838.1, Homo sapiens; XP_001174113.1, Pan troglodytes;XP_851231.1, Canis lupus; NP_001073048.1, Bos taurus; NP_112544.1, Mus musculus; XP_217335.3,Rattus norvegicus; and NP_001032921.1, Gallus gallus.