Mutations

TREM2 c.391+1G>A

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr6:41129000 G>A
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Genomic Region: Intron 2

Findings

This variant, in a homozygous state, was discovered in a Chinese woman suffering from early onset frontotemporal dementia. Symptoms became apparent at 33 years, and included loss of motivation, social withdrawal, inability to concentrate or make appropriate judgements, and changes in appetite and mood. Cognitive impairment followed. When examined at a neurology clinic at age 40, she scored 7/30 on the Mini Mental Status Examination and 29/72 on the frontal behavioral inventory.

The patient was the daughter of consanguineous parents, both of whom were heterozygous carriers of the variant, and who remained clinically healthy. Two unaffected elder siblings were also heterozygous for this variant.

The variant was not detected in 200 cognitively normal controls from the community, nor was it found in ExAc or GnomAD at the time of its publication in 2019.

Imaging and Radiographic Findings

Magnetic resonance imaging revealed cortical atrophy, ventricular enlargement, pronounced thinning of the corpus callosum, and diffuse white-matter hyperintensites. Calcification of the globus pallidus was observed by computed tomography.

Radiography revealed mild bone involvement.

CSF Biomarkers

Core AD biomarkers (Aβ42, total tau, and phospho-tau) were normal. Soluble TREM2 was not detected in the patient’s CSF.

Biological Effect

In heterologous expression systems, this variant was found to cause abnormal splicing (i.e., retention of intron 2). Although TREM2 protein levels were not assayed in these in vitro studies, the lack of soluble TREM2 in the patient’s CSF suggests abnormal protein expression or processing. This variant is classified as likely pathogenic according to the guidelines of the American College of Medical Genetics and Genomics.

Last Updated: 25 Mar 2019

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References

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Further Reading

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Protein Diagram

Primary Papers

  1. Li X, Sun Y, Gong L, Zheng L, Chen K, Zhou Y, Gu Y, Xu Y, Guo Q, Hong Z, Ding D, Fu J, Zhao Q. A novel homozygous mutation in TREM2 found in a Chinese early-onset dementia family with mild bone involvement. Neurobiol Aging. 2019 Jan 24; PubMed.

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