Overview

Pathogenicity: Frontotemporal Dementia : Uncertain Significance, Parkinson's Disease Dementia : Not Classified
Clinical Phenotype: Parkinson's Disease Dementia
Position: (GRCh38/hg38):Chr17:45962350 C>T
Position: (GRCh37/hg19):Chr17:44039716 C>T
dbSNP ID: rs766166210
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 1

Findings

The R5C variant has been identified in at least two individuals with neurodegenerative disease. Initially, it was detected in one of 188 individuals diagnosed with Parkinson’s disease with dementia (Schulte et al., 2015). The carrier had apparently idiopathic PD that presented first with bradykinesia and resting tremor. He later developed rigor, postural instability, and dementia. He had a dizygotic twin brother with life-long essential tremor, but the brother was not available for genotyping. The variant was absent in 188 PD cases without dementia and in 376 controls.

The variant was also found in a study of 261 Chinese Han patients with frontotemporal dementia (FTD). It was observed in one patient who was diagnosed with the behavioral variant of FTD (bvFTD; Nan et al., 2024). The age of disease onset in this male patient was 44 years. He had familial FTD, as did his brother, maternal aunt, and maternal uncle, all of whom are now deceased. The variant was also reported in another study of 49 Chinese Han patients with bvFTD (Liu et al., 2021). These reports may refer to the same individual.

This variant was reported in the gnomAD at a global frequency of 0.000055, including eight heterozygotes of different ancestries (gnomAD 4.1.0, Sep 2024).

Neuropathology

Neuropathological data are unavailable, but magnetic resonance imaging (MRI) revealed slight frontal atrophy and microangiopathy in the patient with PD with dementia, who at the time of the study had a disease duration of 12 years (Schulte et al., 2015). In the 44-year-old patient with bvFTD, who at the time of the study had a disease duration of just half a year, MRI revealed mild atrophy of the bilateral frontal and temporal lobes (Nan et al., 2024). Moreover, 18F‐FDG‐PET revealed hypoperfusion in bilateral frontal and temporal lobes (Liu et al., 2021; Nan et al., 2024).

Biological Effect

The biological effect of this variant is unknown, but multiple in silico algorithms (Polyphen2, SIFT, Mutation Taster, Provean, CADD) predicted a damaging effect (Liu et al., 2021; Nan et al., 2024).  The variant’s PHRED-scaled CADD score which integrates diverse information to predict deleteriousness, was above the commonly used threshold of 20 (20.4, CADD v.1.7, Sep 2024).

Based on the ACMG-AMP guidelines, Nan and colleagues classified this variant as likely pathogenic (Nan et al., 2024).

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References

Paper Citations

1. Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, Meitinger T, Kretzschmar HA, Trenkwalder C, Haass C, Winkelmann J. Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
2. Nan H, Kim YJ, Chu M, Li D, Li J, Jiang D, Wu Y, Ohtsuka T, Wu L. Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations. Alzheimers Res Ther. 2024 Jun 13;16(1):127. PubMed.
3. Liu L, Cui B, Chu M, Cui Y, Jing D, Li D, Xie K, Kong Y, Xia T, Wang C, Wu L. The Frequency of Genetic Mutations Associated With Behavioral Variant Frontotemporal Dementia in Chinese Han Patients. Front Aging Neurosci. 2021;13:699836. Epub 2021 Jul 8 PubMed.

Further Reading

No Available Further Reading