• Test code: 03213
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae Charcot-Marie-Tooth Disease X-linked Panel

Test description

The Invitae Charcot-Marie-Tooth Disease X-Linked Panel analyzes four 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 genes associated with X-linked CMT. 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 covers genes that lead to an X-linked inheritance pattern (i.e., multiple generations are affected, transmission is not male-to-male, and males are generally more severely affected than females). Some clinicians may choose to order this test instead of the broader Invitae Charcot-Marie-Tooth Disease Comprehensive Panel to decrease the chance of detecting variants of uncertain significance.

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Primary panel (4 genes)

Alternative tests to consider

The genes on this panel can also be ordered as part of a broader panel to comprehensively test for Charcot-Marie-Tooth disease. Depending on the individual’s clinical and family history, these broader panels may be appropriate.

Charcot-Marie-Tooth (CMT) disease is a group of hereditary neuropathies characterized by progressive muscle weakness and sensory loss of 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. Hearing loss has been reported in some patients. Patients with X-linked CMT typically have “intermediate” nerve conduction velocities supporting both axonal and demyelinating pathologies. X-linked CMT is inherited in an X-linked pattern. Males are affected whereas females may be mildly affected or unaffected, depending on gene and possibility of skewed X-inactivation.

GeneSubtypeInheritance: X-linkedAdditional information
AIFM1 CMTX4 Axonal neuropathy
GJB1 CMTX1 Intermediate nerve conduction velocities, both males and females are affected, with females exhibiting a later age of onset and milder disease presentation. Causes ~90% of cases of X-linked CMT.
PDK3 CMTX6 Predominantly axonal conduction velocity with variable mild conduction slowing; carrier females may be mildly affected
PRPS1 CMTX5 Variable phenotype including optic atrophy, deafness, and polyneuropathy; females may be severely affected

This test covers the most common genetic cause of X-linked CMT, GJB1 (connexin 32), which causes ~90% of X-linked CMT cases. Other genes that cause rare forms of X-linked CMT are also included in this test.

The CMT subtypes included in this test are all inherited in an X-linked pattern.

Individuals who have inherited a genetic variant that causes X-linked 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. Females are generally less likely than males to show symptoms.

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). 10%-15% of CMT cases are inherited in an X-linked pattern.

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, but the clinical presentations vary by individual and it is difficult to distinguish the subtypes based on presentation alone. Genetic testing enables clinicians to more precisely diagnose the specific subtype of CMT.

  1. 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
  2. Rossor, AM, et al. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol. 2013; 9(10):562-71. PMID: 24018473
  3. Bird, TD. Charcot-Marie-Tooth Hereditary Neuropathy Overview. 1998 Sep 28. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1358/ PMID: 20301532
  4. Braathen, GJ. Genetic epidemiology of Charcot-Marie-Tooth disease. Acta Neurol. Scand., Suppl.c. 2012; :iv-22. doi: 10.1111/ane.12013. PMID: 23106488
  5. Li, J, et al. The PMP22 gene and its related diseases. Mol. Neurobiol. 2013; 47(2):673-98. PMID: 23224996
  6. 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
  7. Pareyson, D, Marchesi, C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009; 8(7):654-67. PMID: 19539237
  8. Saporta, AS, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann. Neurol. 2011; 69(1):22-33. PMID: 21280073
  9. 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
  10. Bird, TD. Charcot-Marie-Tooth Neuropathy X Type 1. 1998 Jun 18. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1374/ PMID: 20301548
  11. Cruse, RP, Hereditary primary motor sensory neuropathies, including Charcot-Marie-Tooth disease. http://www.uptodate.com/contents/hereditary-primary-motor-sensory-neuropathies-including-charcot-marie-tooth-disease Accessed Sept 2015.

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AIFM1 NM_004208.3
GJB1 NM_000166.5
PDK3 NM_001142386.2
PRPS1 NM_002764.3