Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:45996597 A>T
Position: (GRCh37/hg19):Chr17:44073963 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to GTC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 9

Findings

This mutation was identified in a man diagnosed with frontotemporal dementia at age 46 (Shafei et al., 2019). This patient presented with behavioral symptoms and language difficulties, and also showed signs of memory impairment. MRI revealed asymmetric atrophy of the temporal and frontal lobes, with the left side more severely affected than the right. Behavior and cognitive function continued to worsen, and the patient died at age 54.

A family history of dementia was reported, with the proband’s mother and six of her seven siblings said to have developed “dementia” in their 60s or 70s. Genetic data were not available from other family members, precluding segregation analysis.

This mutation was absent in gnomAD and in more than 3000 in-house subjects, including healthy controls and neurological patients with diagnoses other than FTD.

Neuropathology

At autopsy, the patient’s brain showed widespread atrophy, which was particularly severe in the temporal and frontal lobes, the caudate nucleus, the hippocampus, and the amygdala. Tau inclusions—neurofibrillary tangles, pretangles, neuropil threads, and Pick bodies—were found throughout the atrophied regions. Neuronal inclusions were composed of 3R-tau, while astrocytic inclusions contained 4R-tau.

There was no evidence of amyloid deposits or α-synuclein or TDP-43 pathology.

Biological Effect

CADD predicted the D252V variant is deleterious (Shafei et al., 2019).

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References

Paper Citations

1. Shafei R, Woollacott IO, Mummery CJ, Bocchetta M, Guerreiro R, Bras J, Warren JD, Lashley T, Jaunmuktane Z, Rohrer JD. Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia. Neurobiol Aging. 2020 Mar;87:141.e15-141.e20. Epub 2019 Nov 20 PubMed.

Further Reading

No Available Further Reading