ABOUT CHARCOT-MARIE-TOOTH DISEASE

Your feet have always been different — weak, a little numb — and no one ever connected the dots. Turns out, the dots connect to a gene.

Whole genome sequencing identifies the specific genetic cause of CMT, enabling accurate subtype diagnosis, prognosis, medication guidance, and access to gene-specific clinical trials.

PMP22
MFN2
GJB1

About this condition

Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, affecting approximately 1 in 2,500 people. It is characterized by progressive distal muscle weakness and atrophy (typically starting in feet and legs), sensory loss, decreased reflexes, and progressive foot deformities (pes cavus, hammer toes). Onset is typically in the first or second decade of life but varies widely across individuals and genetic subtypes. Severity ranges from mild foot drop to wheelchair dependence, with highly variable progression rates.

The genetic landscape of CMT is profoundly heterogeneous: over 100 distinct genetic subtypes have been described involving more than 45 causative genes. Major inheritance categories include CMT1 (demyelinating, autosomal dominant, ~50% of cases), CMT2 (axonal, ~15–30%, mostly autosomal dominant), and CMTX (X-linked, ~10–15%). The four most commonly mutated genes — PMP22, GJB1, MPZ, and MFN2 — account for approximately 90% of positive molecular diagnoses. PMP22 1.5-Mb duplication causes CMT1A (the most common form); MFN2 mutations cause CMT2A; GJB1 mutations cause CMTX1 with X-linked inheritance patterns.

A genetic diagnosis in CMT is essential for clinical management: accurate subtype classification determines prognosis and progression rate; specific inheritance patterns enable genetic counseling with precise recurrence risks; medication safety changes — vincristine is contraindicated in PMP22-related CMT and can cause severe neuropathy; gene-specific clinical trials (PXT3003 for CMT1A, gene therapy approaches) become accessible; and connection to natural history studies enables informed surveillance and planning. For the substantial portion of CMT patients without a genetic diagnosis, WGS may provide the answer that ends their diagnostic odyssey.

CMT comprises over 100 genetic subtypes with demyelinating, axonal, intermediate, and X-linked forms. The four most common genes account for 90% of diagnoses, but the remaining 10% require comprehensive genetic sequencing.

Gene locus: PMP22 (17p12), MFN2 (1p36.22), GJB1 (Xq13.1)

Standard panels cover 8–20 genes. CMT has 45+ known causes. Step-wise single-gene testing leaves 20–40% undiagnosed.

CMT's extreme genetic heterogeneity defeats step-wise panel testing

CMT genetic testing has historically relied on step-wise approaches: first, PMP22 duplication/deletion analysis (identifies only ~50% of CMT); then, targeted gene panels (8–20 genes, identifying an additional ~30–40%). This leaves 20–40% of patients without a molecular diagnosis. Even comprehensive panels cannot detect all 45+ known CMT genes, rare subtypes, copy number variants beyond PMP22, or intronic variants. Copy number variant detection for the critical PMP22 duplication requires separate analysis not always performed. Whole genome sequencing with proper CNV detection and bioinformatic depth captures all known CMT genes, the PMP22 duplication, intronic variants, and novel candidate genes in a single test.

A genetic diagnosis enables subtype-specific care and clinical trials

Accurate genetic subtyping is transformative: CMT1A (PMP22 duplication) qualifies for gene therapy trials (PXT3003, Phocéa trial); CMT2A (MFN2) qualifies for emerging mitochondrial-targeted therapies in development; CMTX1 (GJB1) requires X-linked inheritance counseling and may qualify for gap junction-targeted approaches. All diagnosed subtypes enable avoidance of neurotoxic medications (vincristine contraindication in PMP22-related disease), accurate prognostic counseling, and surveillance for associated complications. For undiagnosed CMT patients (approximately 40%), WGS often provides the genetic answer that explains their neuropathy and opens access to targeted interventions.

Your feet have always been different — weak, a little numb — and no one ever connected the dots. Turns out, the dots connect to a gene.

Charcot-Marie-Tooth Disease

Standard panels cover 8–20 genes. CMT has 45+ known causes. Step-wise single-gene testing leaves 20–40% undiagnosed.

CMT's extreme genetic heterogeneity defeats step-wise panel testing

A genetic diagnosis enables subtype-specific care and clinical trials

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