Charcot-Marie-Tooth disease: genes and variants

Genes linked to Charcot-Marie-Tooth disease

• LMNA: Prelamin-A/C

  The gene product produces lamins A and C, structural proteins that form the nuclear lamina beneath the inner nuclear membrane. Lamins help maintain nuclear shape and organize chromatin, and LMNA variants are associated with muscular dystrophy, cardiomyopathy, lipodystrophy, and premature-aging syndromes.

  130 disease-causing and 502 uncertain variants in LMNA are linked to Charcot-Marie-Tooth disease.

• MFN2: Mitofusin-2

  It promotes outer-mitochondrial-membrane fusion and coordinates mitochondrial transport, distribution, and contacts with other organelles. Pathogenic variants are a major cause of Charcot-Marie-Tooth disease type 2A and related axonal neuropathies.

  86 disease-causing and 480 uncertain variants in MFN2 are linked to Charcot-Marie-Tooth disease.

• GJB1: Gap junction beta-1 protein

  It forms connexin 32 channels that support metabolic and signaling communication across layers of peripheral myelin produced by Schwann cells. Pathogenic variants cause X-linked Charcot-Marie-Tooth disease type 1, often with transient central nervous system manifestations in some individuals.

  54 disease-causing and 155 uncertain variants in GJB1 are linked to Charcot-Marie-Tooth disease.

• PMP22: Peripheral myelin protein 22

  Its dosage is critical for normal Schwann-cell myelin formation and stability in peripheral nerves. Duplication causes Charcot-Marie-Tooth disease type 1A, deletion causes hereditary neuropathy with liability to pressure palsies, and point variants cause additional neuropathies.

  28 disease-causing and 87 uncertain variants in PMP22 are linked to Charcot-Marie-Tooth disease.

• TTR: Transthyretin

  Its tetramer transports thyroxine and retinol-binding protein, but destabilization can expose aggregation-prone monomers. Pathogenic variants cause hereditary transthyretin amyloidosis affecting peripheral nerves and heart, while wild-type protein can also form cardiac amyloid with aging.

  3 disease-causing and 5 uncertain variants in TTR are linked to Charcot-Marie-Tooth disease.

• 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.

  2 disease-causing and 2 uncertain variants in VCP are linked to Charcot-Marie-Tooth disease.

• KIF5A: Kinesin heavy chain isoform 5A

  It drives anterograde transport of organelles and proteins along axonal microtubules and is especially important in long motor neurons. Pathogenic variants can cause hereditary spastic paraplegia, axonal Charcot-Marie-Tooth disease, or amyotrophic lateral sclerosis depending on the affected region and mechanism.

  1 disease-causing and 0 uncertain variants in KIF5A are linked to Charcot-Marie-Tooth disease.

• NTRK1: High affinity nerve growth factor receptor

  Nerve-growth-factor signaling through this pathway supports survival and differentiation of sensory and sympathetic neurons. Loss-of-function variants cause congenital insensitivity to pain with anhidrosis, whereas oncogenic NTRK1 fusions can drive diverse cancers.

  0 disease-causing and 8 uncertain variants in NTRK1 are linked to Charcot-Marie-Tooth disease.

Weakly linked (only a few uncertain records): SETX, POLG, DNMT1, ATP7A, COL6A2, GABRG2, GLA and LAMA2.

Where Charcot-Marie-Tooth disease variants cluster

• MFN2 Dynamin-type G (positions 93–342): 57 of 86 disease-causing changes, 2.0× more than its size predicts.
• LMNA Coil 1A (positions 34–70): 23 of 130 disease-causing changes, 3.2× more than its size predicts.
• MFN2 Part of a helix bundle domain, formed by helices (positions 359–385): 12 of 86 disease-causing changes, 3.9× more than its size predicts.
• GJB1 Extracellular (positions 154–191): 16 of 54 disease-causing changes, 2.2× more than its size predicts.
• LMNA Head (positions 1–33): 15 of 130 disease-causing changes, 2.3× more than its size predicts.

Known disease-causing variants in Charcot-Marie-Tooth disease

Showing 60 of 304.

Uncertain variants in Charcot-Marie-Tooth disease that look disease-causing

Which prediction tools work for Charcot-Marie-Tooth disease

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

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 94 out of 100
• CADD: 92 out of 100
• MetaLR: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 87 out of 100
• PolyPhen-2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 84 out of 100
• phyloP: 83 out of 100

Same protein, different disease

• Dilated cardiomyopathy is also caused by LMNA variants; they fall in the same places as the Charcot-Marie-Tooth disease variants (21 disease-causing).
• Familial partial lipodystrophy, Dunnigan type is also caused by LMNA variants; they fall in the same places as the Charcot-Marie-Tooth disease variants (13 disease-causing).
• Emery-Dreifuss muscular dystrophy is also caused by LMNA variants; they fall in the same places as the Charcot-Marie-Tooth disease variants (12 disease-causing).
• Congenital muscular dystrophy due to LMNA mutation is also caused by LMNA variants; they fall in the same places as the Charcot-Marie-Tooth disease variants (11 disease-causing).
• Hutchinson-Gilford syndrome is also caused by LMNA variants; they fall partly in the same places as the Charcot-Marie-Tooth disease variants (9 disease-causing).
• Charcot-Marie-Tooth disease type 2A2 is also caused by MFN2 variants; they fall partly in the same places as the Charcot-Marie-Tooth disease variants (32 disease-causing).
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; is also caused by MFN2 variants; they fall in the same places as the Charcot-Marie-Tooth disease variants (9 disease-causing).
• Charcot-Marie-Tooth Neuropathy X is also caused by GJB1 variants; they fall in the same places as the Charcot-Marie-Tooth disease variants (90 disease-causing).
• Amyloidosis, hereditary systemic 1 is also caused by TTR variants; they fall mostly in different places as the Charcot-Marie-Tooth disease variants (101 disease-causing).
• Carpal tunnel syndrome is also caused by TTR variants; they fall mostly in different places as the Charcot-Marie-Tooth disease variants (8 disease-causing).
• Hyperthyroxinemia, dystransthyretinemic is also caused by TTR variants; they fall mostly in different places as the Charcot-Marie-Tooth disease variants (7 disease-causing).
• Inclusion body myopathy with Paget disease of bone and frontotemporal dementia is also caused by VCP variants; they fall mostly in different places as the Charcot-Marie-Tooth disease variants (31 disease-causing).
• Frontotemporal dementia and/or amyotrophic lateral sclerosis is also caused by VCP variants; they fall mostly in different places as the Charcot-Marie-Tooth disease variants (30 disease-causing).
• Childhood Onset VCP-related Neurodevelopmental Disorder is also caused by VCP variants; they fall mostly in different places as the Charcot-Marie-Tooth disease variants (4 disease-causing).

Diseases related to Charcot-Marie-Tooth disease

• Peripheral neuropathy, also linked to GJB1, KIF5A and MFN2
• Amyotrophic lateral sclerosis, also linked to KIF5A and VCP
• Auditory neuropathy, also linked to KIF5A and MFN2
• Hereditary spastic paraplegia, also linked to KIF5A
• Alzheimer disease, also linked to VCP
• Dilated cardiomyopathy, also linked to LMNA
• Amyloidosis, hereditary systemic 1, also linked to TTR
• Bethlem myopathy, also linked to LMNA
• Charcot-Marie-Tooth Neuropathy X, also linked to GJB1
• Primary dilated cardiomyopathy, also linked to LMNA
• Ovarian cancer, also linked to NTRK1
• Frontotemporal dementia and/or amyotrophic lateral sclerosis, also linked to VCP

Frequently asked questions

Which genes are linked to Charcot-Marie-Tooth disease?

In CATVariant, Charcot-Marie-Tooth disease is linked to 8 analyzed proteins: LMNA (Prelamin-A/C), MFN2 (Mitofusin-2), GJB1 (Gap junction beta-1 protein), PMP22 (Peripheral myelin protein 22), TTR (Transthyretin), VCP (Transitional endoplasmic reticulum ATPase) and 2 more.

How many genetic variants are linked to Charcot-Marie-Tooth disease?

1,711 variants: 304 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,253 are of uncertain significance or have conflicting reports.

Which uncertain variants in Charcot-Marie-Tooth disease look disease-causing?

27 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example PMP22 R157Q, PMP22 T23M, LMNA R41L, LMNA A43T and PMP22 M69T. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Charcot-Marie-Tooth disease?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 231 disease-causing and 80 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.

Download every variant as CSV · Browse all diseases · Methods · About the Center