Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, BP4
Clinical Phenotype Studied: Corticobasal Syndrome, Corticobasal Degeneration, Progressive Supranuclear Palsy, bvFTD
Position: (GRCh38/hg38):Chr17:46010375 T>C
Position: (GRCh37/hg19):Chr17:44087741 T>C
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750912
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Silent
Codon Change: AAT to AAC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This silent mutation was first reported in a woman with a frontotemporal dementia (FTD) syndrome resembling corticobasal degeneration (CBD; Spillantini et al., 2000). The mutation carrier belonged to a previously described kindred affected by early onset dementia. The reported pedigree shows four affected family members over three generations (Brown et al., 1996). Segregation with disease could not be determined. The proband experienced symptom onset at age 56, starting with personality changes, cognitive decline, and stereotyped behavior. She also developed supranuclear gaze palsy, bradykinesia, and muteness. She died at age 69, 13 years after symptom onset.

This mutation was later described in a Japanese man with probable progressive supranuclear palsy (PSP; Ogaki et al., 2012). He had a family history of neurodegenerative disease, but segregation with disease could not be determined. He developed symptoms at age 44, starting with parkinsonism. Motor symptoms included bradykinesia, rigidity, and postural instability. He developed dementia accompanied by changes in personality and behavior.

This variant has also been identified in a Chinese man with the behavioral variant of FTD (bvFTD) whose symptoms emerged at age 46 (Nan et al., 2024). His sister and mother were also affected.

In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, three families, including six presumed carriers, were reported (Moore et al., 2020, suppl tables 5-6). Data included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype. Mean age at onset was 49.3 years and the mean age at death was 64.3 years for three affected individuals. One of the presumed carriers was diagnosed with bvFTD, one with corticobasal syndrome, one with PSP, and three with dementia not otherwise specified. Of note, the families and individuals reported in this study may overlap with the ones described above.

This variant was absent from the gnomAD public variant database (gnomAD v4.1.1, Apr 2024).

Neuropathology

Autopsy of the female proband originally described by Spillantini and colleagues showed marked frontotemporal atrophy with prominent neuronal loss in the globus pallidus, substantia nigra, and locus coeruleus. Swollen achromatic neurons and tau-positive inclusions were present throughout the brain. Plaques and tangles were rare in the hippocampus and cerebral cortex. Overall, the neuropathology was most consistent with CBD (Spillantini et al., 2000; Brown et al., 1996).

The Chinese carrier showed bilateral frontal and temporal lobe atrophy as assessed by MRI (Nan et al., 2024).

Biological Effect

Several studies have shown that the N296N silent mutation increases the inclusion of exon 10 in tau mRNA and therefore increases the ratio of 4R/3R tau protein (Spillantini et al., 2000; Grover et al., 2002; Tubeuf et al., 2020).

This variant was predicted to be benign by some in silico algorithms, including Mutation Tasting, SIFT, Provean, and PolyPhen-2 (Nan et al., 2024) and its PHRED-scaled CADD score, which integrates diverse information in silico, was below the commonly used threshold of 20 to predict deleteriousness (12.98; CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Likely Pathogenic*

*Clinical phenotypes varied between carriers.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Spillantini MG, Yoshida H, Rizzini C, Lantos PL, Khan N, Rossor MN, Goedert M, Brown J. A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann Neurol. 2000 Dec;48(6):939-43. PubMed.
2. Brown J, Lantos PL, Roques P, Fidani L, Rossor MN. Familial dementia with swollen achromatic neurons and corticobasal inclusion bodies: a clinical and pathological study. J Neurol Sci. 1996 Jan;135(1):21-30. PubMed.
3. Ogaki K, Li Y, Takanashi M, Ishikawa KI, Kobayashi T, Nonaka T, Hasegawa M, Kishi M, Yoshino H, Funayama M, Tsukamoto T, Shioya K, Yokochi M, Imai H, Sasaki R, Kokubo Y, Kuzuhara S, Motoi Y, Tomiyama H, Hattori N. Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. Parkinsonism Relat Disord. 2012 Jul 18; PubMed.
4. 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.
5. Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, Van Deerlin VM, Warren JD, Fox NC, Rossor MN, Mead S, Bocchetta M, Boeve BF, Knopman DS, Graff-Radford NR, Forsberg LK, Rademakers R, Wszolek ZK, van Swieten JC, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Snowden JS, Saxon J, Jones M, Pickering-Brown S, Le Ber I, Camuzat A, Brice A, Caroppo P, Ghidoni R, Pievani M, Benussi L, Binetti G, Dickerson BC, Lucente D, Krivensky S, Graff C, Öijerstedt L, Fallström M, Thonberg H, Ghoshal N, Morris JC, Borroni B, Benussi A, Padovani A, Galimberti D, Scarpini E, Fumagalli GG, Mackenzie IR, Hsiung GR, Sengdy P, Boxer AL, Rosen H, Taylor JB, Synofzik M, Wilke C, Sulzer P, Hodges JR, Halliday G, Kwok J, Sanchez-Valle R, Lladó A, Borrego-Ecija S, Santana I, Almeida MR, Tábuas-Pereira M, Moreno F, Barandiaran M, Indakoetxea B, Levin J, Danek A, Rowe JB, Cope TE, Otto M, Anderl-Straub S, de Mendonça A, Maruta C, Masellis M, Black SE, Couratier P, Lautrette G, Huey ED, Sorbi S, Nacmias B, Laforce R Jr, Tremblay ML, Vandenberghe R, Damme PV, Rogalski EJ, Weintraub S, Gerhard A, Onyike CU, Ducharme S, Papageorgiou SG, Ng AS, Brodtmann A, Finger E, Guerreiro R, Bras J, Rohrer JD, FTD Prevention Initiative. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020 Feb;19(2):145-156. Epub 2019 Dec 3 PubMed.
6. Grover A, DeTure M, Yen SH, Hutton M. Effects on splicing and protein function of three mutations in codon N296 of tau in vitro. Neurosci Lett. 2002 Apr 19;323(1):33-6. PubMed.
7. Tubeuf H, Charbonnier C, Soukarieh O, Blavier A, Lefebvre A, Dauchel H, Frebourg T, Gaildrat P, Martins A. Large-scale comparative evaluation of user-friendly tools for predicting variant-induced alterations of splicing regulatory elements. Hum Mutat. 2020 Oct;41(10):1811-1829. Epub 2020 Aug 16 PubMed.

Further Reading

No Available Further Reading