Frontotemporal dementia: genes and variants

Genes linked to Frontotemporal dementia

• PSEN1: Presenilin-1

  Its catalytic activity within gamma-secretase cleaves APP and many other membrane proteins, including Notch receptors. Pathogenic variants alter amyloid-beta production and are the most common known cause of autosomal dominant early-onset Alzheimer disease.

  63 disease-causing and 62 uncertain variants in PSEN1 are linked to Frontotemporal dementia.

• MAPT: Microtubule-associated protein tau

  Its tau isoforms stabilize and organize neuronal microtubules, especially in axons, while also participating in transport and signaling. Pathogenic variants cause inherited frontotemporal dementia, and abnormal tau aggregation defines multiple neurodegenerative tauopathies.

  17 disease-causing and 105 uncertain variants in MAPT are linked to Frontotemporal dementia.

• GRN: Progranulin

  It is secreted and proteolytically processed into granulins and has roles in lysosomal function, inflammation, neuronal survival, and tissue repair. Heterozygous loss-of-function variants cause frontotemporal dementia through progranulin haploinsufficiency, while biallelic loss causes neuronal ceroid lipofuscinosis.

  0 disease-causing and 0 uncertain variants in GRN are linked to Frontotemporal dementia.

Weakly linked (only a few uncertain records): SETX, CSF1R and OPTN.

Where Frontotemporal dementia variants cluster

• MAPT Microtubule-binding domain (positions 561–685): 14 of 17 disease-causing changes, 5.0× more than its size predicts.
• PSEN1 Transmembrane (positions 249–272): 12 of 63 disease-causing changes, 3.7× more than its size predicts.
• PSEN1 Transmembrane (positions 133–153): 7 of 63 disease-causing changes, 2.5× more than its size predicts.
• PSEN1 Lumenal (positions 104–132): 8 of 63 disease-causing changes, 2.0× more than its size predicts.
• PSEN1 Transmembrane (positions 83–103): 6 of 63 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Frontotemporal dementia

Showing 60 of 80.

Uncertain variants in Frontotemporal dementia that look disease-causing

Which prediction tools work for Frontotemporal dementia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 97 out of 100
• MetaLR: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 92 out of 100
• EVE: 89 out of 100
• phyloP: 88 out of 100
• SIFT: 86 out of 100

Same protein, different disease

• Alzheimer disease is also caused by PSEN1 variants; they fall in the same places as the Frontotemporal dementia variants (88 disease-causing).
• Pick disease is also caused by PSEN1 variants; they fall in the same places as the Frontotemporal dementia variants (26 disease-causing).
• Supranuclear palsy, progressive, 1 is also caused by MAPT variants; they fall partly in the same places as the Frontotemporal dementia variants (6 disease-causing).

Diseases related to Frontotemporal dementia

• Alzheimer disease, also linked to GRN, MAPT and PSEN1
• Pick disease, also linked to MAPT and PSEN1
• Dementia, also linked to GRN and PSEN1
• Telangiectasia, hereditary hemorrhagic, type 2, also linked to PSEN1
• Dilated cardiomyopathy, also linked to PSEN1
• Acne inversa, familial, 3, also linked to PSEN1
• Neuronal ceroid lipofuscinosis, also linked to GRN
• Parkinson disease, late-onset, also linked to MAPT
• Supranuclear palsy, progressive, 1, also linked to MAPT
• GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, also linked to GRN
• Familial isolated dilated cardiomyopathy, also linked to PSEN1
• Early-onset autosomal dominant Alzheimer disease, also linked to PSEN1

Frequently asked questions

Which genes are linked to Frontotemporal dementia?

In CATVariant, Frontotemporal dementia is linked to 3 analyzed proteins: PSEN1 (Presenilin-1), MAPT (Microtubule-associated protein tau) and GRN (Progranulin).

How many genetic variants are linked to Frontotemporal dementia?

283 variants: 80 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 169 are of uncertain significance or have conflicting reports.

Which uncertain variants in Frontotemporal dementia look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example PSEN1 A260G. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Frontotemporal dementia?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 68 disease-causing and 39 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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