Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr6:41130778 AGG>---
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Deletion
Expected RNA Consequence: Splicing Alteration
Genomic Region: Intron 1

Findings

This variant creates a three-nucleotide deletion in the 5′ consensus donor splice site in intron 1. The homozygous variant was identified in three siblings affected by early onset dementia, members of a consanguineous Lebanese family (Chouery et al., 2008). Symptom onset occurred at 30–35 years of age, and included forgetfulness, fatigue, lack of initiative, and inability to perform activities of daily living. Clinical progression was characterized by euphoria, loss of social inhibition, and incontinence, followed by severe dementia. One patient died at age 50, a second at age 46 due to respiratory infection, and the third was in a vegetative state at age 50. Additional genotyping of 11 unaffected family members showed that this sequence variation segregated with the disease phenotype. The variant was not found in 200 control chromosomes from Lebanese subjects.

Neuropathology

Neuropathological characterization of patients carrying this variant is currently lacking. However, MRI revealed brain atrophy, including thinning of the corpus callosum, but not the calcification typically seen in Nasu-Hakola disease; nor were bone cysts seen in these patients (Chouery et al., 2008).

Biological Effect

This variant resulted in a greater than twofold reduction in the level of TREM2 transcripts in lymphocytes and fibroblasts, as compared to controls. Abnormal transcripts were not detected, but the authors could not rule out the possibility that the variant leads to some degree of aberrant splicing (Chouery et al., 2008).

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References

Paper Citations

1. Chouery E, Delague V, Bergougnoux A, Koussa S, Serre JL, Mégarbané A. Mutations in TREM2 lead to pure early-onset dementia without bone cysts. Hum Mutat. 2008 Sep;29(9):E194-204. PubMed.

Further Reading

No Available Further Reading