Frontotemporal dementia and/or amyotrophic lateral sclerosis: genes and variants

Genes linked to Frontotemporal dementia and/or amyotrophic lateral sclerosis

• VCP: Transitional endoplasmic reticulum ATPase

  It uses ATP to extract ubiquitinated proteins from complexes or membranes for recycling or degradation and is central to proteostasis, ER-associated degradation, and autophagy. Dominant pathogenic variants cause multisystem proteinopathy with inclusion-body myopathy, Paget disease, frontotemporal dementia, or ALS.

  30 disease-causing and 137 uncertain variants in VCP are linked to Frontotemporal dementia and/or amyotrophic lateral sclerosis.

• SQSTM1: Sequestosome-1

  SQSTM1, also called p62, is an adapter that connects ubiquitinated cargo to autophagosomes for selective autophagy. It also influences the NRF2 cytoprotective pathway and endosomal organization, and SQSTM1 variants are associated with Paget disease of bone and neurodegeneration.

  4 disease-causing and 319 uncertain variants in SQSTM1 are linked to Frontotemporal dementia and/or amyotrophic lateral sclerosis.

• TBK1: Serine/threonine-protein kinase TBK1

  It activates IRF3 and related antiviral pathways after innate immune sensing and also participates in autophagy and cellular homeostasis. Loss-of-function variants can cause amyotrophic lateral sclerosis or frontotemporal dementia, while increased pathway activity can support inflammatory disease and some cancers.

  4 disease-causing and 180 uncertain variants in TBK1 are linked to Frontotemporal dementia and/or amyotrophic lateral sclerosis.

• C9ORF72: Guanine nucleotide exchange factor C9orf72

  It participates in endolysosomal trafficking, autophagy, and immune regulation through complexes with SMCR8 and WDR41. A large GGGGCC repeat expansion causes the most common inherited form of amyotrophic lateral sclerosis and frontotemporal dementia.

  0 disease-causing and 12 uncertain variants in C9ORF72 are linked to Frontotemporal dementia and/or amyotrophic lateral sclerosis.

Weakly linked (only a few uncertain records): GRN and KIF5A.

Known disease-causing variants in Frontotemporal dementia and/or amyotrophic lateral sclerosis

Uncertain variants in Frontotemporal dementia and/or amyotrophic lateral sclerosis that look disease-causing

Which prediction tools work for Frontotemporal dementia and/or amyotrophic lateral sclerosis

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

• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• SIFT: 81 out of 100
• phyloP: 77 out of 100

Same protein, different disease

• Childhood Onset VCP-related Neurodevelopmental Disorder is also caused by VCP variants; they fall mostly in different places as the Frontotemporal dementia and/or amyotrophic lateral sclerosis variants (4 disease-causing).

Diseases related to Frontotemporal dementia and/or amyotrophic lateral sclerosis

• Amyotrophic lateral sclerosis, also linked to C9ORF72, SQSTM1, TBK1 and VCP
• Charcot-Marie-Tooth disease, also linked to VCP
• Alzheimer disease, also linked to VCP
• Inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also linked to VCP
• Motor neuron disease, also linked to TBK1
• Childhood Onset VCP-related Neurodevelopmental Disorder, also linked to VCP
• Paget disease of bone 2, early-onset, also linked to SQSTM1
• Paget disease of bone 3, also linked to SQSTM1
• Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, also linked to SQSTM1

Frequently asked questions

Which genes are linked to Frontotemporal dementia and/or amyotrophic lateral sclerosis?

In CATVariant, Frontotemporal dementia and/or amyotrophic lateral sclerosis is linked to 4 analyzed proteins: VCP (Transitional endoplasmic reticulum ATPase), SQSTM1 (Sequestosome-1), TBK1 (Serine/threonine-protein kinase TBK1) and C9ORF72 (Guanine nucleotide exchange factor C9orf72).

How many genetic variants are linked to Frontotemporal dementia and/or amyotrophic lateral sclerosis?

743 variants: 38 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 650 are of uncertain significance or have conflicting reports.

Which uncertain variants in Frontotemporal dementia and/or amyotrophic lateral sclerosis look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example VCP R93H and VCP R89W. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Frontotemporal dementia and/or amyotrophic lateral sclerosis?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 18 disease-causing and 98 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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