Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46024011_46024022 GGGCGGAGATCG>-
Position: (GRCh37/hg19):Chr17:44101377_44101388 GGGCGGAGATCG>-
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: GGG.GCG.GAG.ATC.GTG to GTG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13

Findings

This variant was identified in a woman diagnosed with frontotemporal dementia at age 49, with a two-year history of behavioral changes and decline in language function (Shafei et al., 2019). MRI revealed bilateral frontal and temporal lobe atrophy. Behavior and cognition continued to decline, and she required full-time care within three years of her diagnosis. She died at age 54.

The patient’s mother, who died in middle age, was reported to have shown aggressive behavior. Her maternal grandmother exhibited signs of dementia and behavioral changes beginning in her early 50s; she died at age 70.

The proband was found to carry a heterozygous deletion of 12 nucleotides in exon 13 of the MAPT gene. This deletion results in the removal of four amino acids, without a frameshift. Genetic data were not available from other family members, precluding segregation analysis.

This mutation was absent in gnomAD and in more than 3,000 in-house subjects including healthy controls and neurological patients with diagnoses other than FTD.

Neuropathology

At autopsy, the patient’s brain showed severe atrophy of the frontal and temporal lobes, hippocampus, and amygdala. Neurofibrillary tangles, neuropil threads, Pick bodies, and astrocytic inclusions were observed throughout the brain; neuronal and astrocytic inclusions were composed of 3R-tau.

Occasional amyloid deposits occurred in the parenchyma, while α-synuclein and TDP-43 pathology were absent.

Biological Effect

CADD predicted this 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