Invitae Charcot-Marie-Tooth Disease Comprehensive Panel


Test description

The Invitae Charcot-Marie-Tooth Disease Comprehensive Panel analyzes up to 45 genes associated with Charcot-Marie-Tooth (CMT) disease, a hereditary neuropathy. These genes were curated based on the available evidence to date to provide a comprehensive test for this condition.

Individuals with clinical signs and symptoms of CMT may benefit from diagnostic genetic testing to confirm the diagnosis, provide anticipatory guidance, help determine which relatives are at risk, or qualify affected patients to enroll in certain clinical trials. This test is Invitae’s broadest CMT panel. Because this panel covers genes with dominant, recessive, and X-linked inheritance patterns, it is particularly helpful if the inheritance pattern is unclear from the patient’s family history.

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Primary panel (42 genes)


INF2: Readthrough analysis is not offered for exon 8.

Add-on preliminary-evidence genes (3 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.


Alternative tests to consider

For a broader analysis of the genetics of hereditary neuropathies:

Testing for hereditary spastic paraplegia may also be considered if the patient exhibits clinical overlap with this disorder.

Charcot-Marie-Tooth (CMT) disease is a group of hereditary neuropathies characterized by progressive muscle weakness and sensory loss in the arms and legs. Individuals in the early stages of the disease often present with clumsiness due to numbness in the feet. As the disease progresses, the lack of nerve conduction to the extremities can also result in depressed tendon reflexes, muscle atrophy—especially at the ankles and hands, and foot deformities such as high, arched feet or hammertoes. Symptoms are caused by the impairment of the ability of peripheral nerves to conduct signals throughout the body, which results in reduced motor control and sensation in the arms and legs, especially at the ankles and wrists. Different subtypes of CMT are caused by different types of peripheral nerve abnormalities: abnormalities in the peripheral nerve axons (axonal types), abnormalities in the myelin sheath that insulates peripheral nerve axons (demyelinating types), or (rarely) both types of abnormalities (intermediate). Nerve conduction studies can be used in combination with inheritance pattern to determine the type of CMT (CMT1, 2, 4, X, or dominant intermediate), but genetic testing is needed to identify the specific subtype (e.g., CMT1A versus CMT1B).

GeneSubtypeInheritanceAdditional information
Autosomal dominantAutosomal recessiveX-linked
AARS CMT2N axonal neuropathy
AIFM1 CMTX4 axonal neuropathy
BSCL2 CMT2 axonal neuropathy
DNAJB2 CMT2T axonal neuropathy
DNM2 DI-CMTB intermediate nerve conduction velocities
DYNC1H1 CMT2O axonal neuropathy
EGR2 CMT1D, CMT4E demyelinating neuropathy
FGD4 CMT4H demyelinating neuropathy
FIG4 CMT4J combined axonal and demyelinating neuropathy
GARS CMT2D axonal neuropathy
GDAP1 CMT2H/2K, CMT4A variable nerve conduction velocities, ranging from demyelinating to axonal neuropathy – accounts for ~1% of CMT
GJB1 CMT1X intermediate nerve conduction velocities, both males and females affected, with females exhibiting a later age of onset and milder disease presentation, accounts for ~8% of CMT
GNB4 DI-CMTF variable nerve conduction velocities, ranging from demyelinating to axonal neuropathy
HARS CMT2W axonal neuropathy
HINT1 neuromyotonia and axonal neuropathy axonal neuropathy
HSPB1 CMT2F axonal neuropathy
HSPB8 CMT2L axonal neuropathy
IGHMBP2 CMT2S axonal neuropathy
INF2 DI-CMTE intermediate nerve conduction velocities
LITAF CMT1C demyelinating neuropathy
LMNA CMT2B1 axonal neuropathy
LRSAM1 CMT2P axonal neuropathy
MARS* CMT2U axonal neuropathy
MED25 CMT2B2 axonal neuropathy
MFN2 CMT2A2 axonal neuropathy, accounts for ~2% of CMT
MORC2 CMT2Z axonal neuropathy
MPZ CMT1B, CMT2I, CMT2J, DI-CMTD variable nerve conduction velocities, ranging from demyelinating to axonal neuropathy, accounts for ~2% of CMT
MTMR2 CMT4B1 demyelinating neuropathy
NDRG1 CMT4D demyelinating neuropathy
NEFL CMT2E, CMT1F variable nerve conduction velocities, ranging from demyelinating to axonal neuropathy
PDK3 CMTX6 predominantly axonal conduction velocity with variable mild conduction slowing, carrier females may be mildly affected.
PLEKHG5 RI-CMTC variable nerve conduction velocities, ranging from demyelinating to axonal neuropathy
PMP22 CMT1A, CMT1E, HNPP demyelinating neuropathy, accounts for a majority of positive findings
PRPS1 CMTX5 variable phenotype including optic atrophy, deafness, and polyneuropathy, females can be severely affected.
PRX CMT4F demyelinating neuropathy
RAB7A CMT2B axonal neuropathy
SBF2 CMT4B2 demyelinating neuropathy
SH3TC2 CMT4C demyelinating neuropathy
SLC25A46* CMT6B axonal neuropathy
SPG11 CMT2X axonal neuropathy
SURF1* CMT4K demyelinating neuropathy
TFG HMNSO axonal neuropathy
TRIM2 CMT2R axonal neuropathy
TRPV4 CMT2C axonal neuropathy
YARS DI-CMTC variable nerve conduction velocities, ranging from demyelinating to axonal neuropathy

*Preliminary-evidence gene

This panel covers the most common genes associated with CMT types 1, 2, 4, X, and dominant intermediate. Across all types of CMT, four genes account for the majority of cases (50%-75%): PMP22, MPZ, GJB1, and MFN2. Other genes that have been identified as rare causes of CMT are also included in this test and contribute to a higher detection rate, though the exact contribution of these additional genes is not known.

CMT can be inherited in an autosomal dominant, autosomal recessive, or an X-linked pattern.

CMT is a highly penetrant condition, and individuals who have inherited a genetic variant that causes CMT are extremely likely to develop symptoms at some point in their lifetimes; however, the age of onset and the severity of symptoms are difficult to predict. Significant intra-family variability with respect to age of onset, symptoms and disease progression has been observed.

Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system. Overall prevalence of CMT is usually reported as 1 in 2,500, although several more recent epidemiological studies reported prevalences of CMT ranging from 1 in 1,214 (in Norway) to 1 in 6,500 (in the United Kingdom). It is possible these figures may be an underestimation of the prevalence of CMT due to under-diagnosis of mild or late-onset cases.

Subtypes of CMT can be partially distinguished by inheritance pattern and the use of nerve conduction studies. These different subtypes can be associated with different disease severities and symptoms; however, clinical presentation can vary even within a subtype, making it difficult to distinguish the subtypes based on presentation alone. Genetic testing enables clinicians to more precisely diagnose the specific subtype of CMT.

  1. Bergamin, G, et al. Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal charcot-marie-tooth disease. Neuromolecular Med. 2014; 16(3):540-50. doi: 10.1007/s12017-014-8307-9. PMID: 24819634
  2. Braathen, GJ. Genetic epidemiology of Charcot-Marie-Tooth disease. Acta Neurol. Scand., Suppl.c. 2012; :iv-22. doi: 10.1111/ane.12013. PMID: 23106488
  3. DiVincenzo, C, et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014; 2(6):522-9. doi: 10.1002/mgg3.106. PMID: 25614874
  4. Li, J, et al. The PMP22 gene and its related diseases. Mol. Neurobiol. 2013; 47(2):673-98. PMID: 23224996
  5. Neefjes, J, van, der, Kant, R. Stuck in traffic: an emerging theme in diseases of the nervous system. Trends Neurosci. 2014; 37(2):66-76. PMID: 24411104
  6. Pareyson, D, Marchesi, C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009; 8(7):654-67. PMID: 19539237
  7. Rossor, AM, et al. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol. 2013; 9(10):562-71. PMID: 24018473
  8. Saporta, AS, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann. Neurol. 2011; 69(1):22-33. PMID: 21280073
  9. Szigeti, K, et al. Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genet. Med. 2006; 8(2):86-92. PMID: 16481890
  10. Timmerman, V, et al. Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias. Exp. Neurol. 2013; 246:14-25. PMID: 22285450

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AARS NM_001605.2
AIFM1 NM_004208.3
BSCL2 NM_032667.6
DNAJB2 NM_001039550.1
DNM2 NM_001005360.2
DYNC1H1 NM_001376.4
EGR2 NM_000399.3
FGD4 NM_139241.3
FIG4 NM_014845.5
GARS NM_002047.2
GDAP1 NM_018972.2
GJB1 NM_000166.5
GNB4 NM_021629.3
HARS NM_002109.5
HINT1 NM_005340.6
HSPB1 NM_001540.3
HSPB8 NM_014365.2
IGHMBP2 NM_002180.2
INF2* NM_022489.3
LITAF NM_004862.3
LMNA NM_170707.3
LRSAM1 NM_138361.5
MARS NM_004990.3
MED25 NM_030973.3
MFN2 NM_014874.3
MORC2 NM_014941.2
MPZ NM_000530.6
MTMR2 NM_016156.5
NDRG1 NM_006096.3
NEFL NM_006158.4
PDK3 NM_001142386.2
PLEKHG5 NM_020631.4
PMP22 NM_000304.3
PRPS1 NM_002764.3
PRX NM_181882.2
RAB7A NM_004637.5
SBF2 NM_030962.3
SH3TC2 NM_024577.3
SLC25A46 NM_138773.2
SPG11 NM_025137.3
SURF1 NM_003172.3
TFG NM_006070.5
TRIM2 NM_001130067.1
TRPV4 NM_021625.4
YARS NM_003680.3

INF2: Readthrough analysis is not offered for exon 8.