Charcot-Marie-Tooth Neuropathy Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: NE1301

The Blueprint Genetics Charcot-Marie-Tooth Neuropathy Panel is an 86 gene test for genetic diagnostics of patients with clinical suspicion of Charcot-Marie-Tooth neuropathy.

Charcot-Marie-Tooth (CMT) neuropathy, also called hereditary motor/sensory neuropathy (HMSN), is the most common genetic cause of neuropathy. Prevalence is estimated to be 1:3300. CMT is characterized by broad genetic heterogeneity and can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. The prevalence of genetic subtypes differs in different countries and therefore the clinical utility of this comprehensive gene panel covering all inheritance patterns is high and serves all patients with clinical suspicion of CMT. Genetic counseling and family member testing is possible after the genetic cause of the disease is known. In rare cases the gene mutation causing CMT can be de novo.

About Charcot-Marie-Tooth Neuropathy

CMT neuropathy results from involvement of peripheral nerves that can affect the motor system and/or the sensory system. Individuals with CMT experience symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands. Pes cavus foot deformity is common. CMT neuropathies can be divided to demyelination and axonal forms.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Charcot-Marie-Tooth Neuropathy Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
AARS Epileptic encephalopathy, early infantile, Charcot-Marie-Tooth disease AD/AR 5 14
AIFM1 Deafness XL 27 23
AMACR Alpha-methylacyl-CoA racemase deficiency, Bile acid synthesis defect AR 3 8
ARHGEF10 Slowed nerve conduction velocity AD 3 10
ATL1 Spastic paraplegia, Neuropathy, hereditary sensory AD 23 75
ATL3 Neuropathy, hereditary sensory AD 1 4
ATP7A Menkes disease XL 109 353
BAG3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 30 50
BSCL2 Lipodystrophy, congenital generalized, Encephalopathy, progressive AR 29 46
C12ORF65 Spastic paraplegia, Combined oxidative phosphorylation deficiency AR 10 10
CCT5 Neuropathy, hereditary sensory, with spastic paraplegia AR 1 1
COX6A1 Charcot-Marie-Tooth disease AR 1 1
COX10* Leigh syndrome, Mitochondrial complex IV deficiency AR 48 13
CTDP1 Congenital cataracts, facial dysmorphism, and neuropathy AR 1 1
DCAF8 AD 1 1
DCTN1 Perry syndrome, Neuropathy, distal hereditary motor AD 11 39
DHTKD1 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease AD/AR 7 18
DNM2 Myopathy, Lethal akinesia and musculoskeletal abnormalities, with brain and retinal hemorrhages, Charcot-Marie-Tooth disease AD/AR 26 45
DNMT1 Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy AD 10 19
DST Neuropathy, hereditary sensory and autonomic AR 5 6
DYNC1H1 Spinal muscular atrophy, Charcot-Marie-Tooth disease, Mental retardation AD 49 60
EGR2 Neuropathy, Dejerine-Sottas disease, Charcot-Marie-Tooth disease AD/AR 13 20
FAM134B Neuropathy, hereditary sensory and autonomic AR 8 5
FBLN5 Cutis laxa, Macular degeneration, age-related AD/AR 13 21
FGD4 Charcot-Marie-Tooth disease AR 15 26
FIG4 Amyotrophic lateral sclerosis, Polymicrogyria, bilateral occipital, Yunis-Varon syndrome, Charcot-Marie-Tooth disease AD/AR 26 58
FXN* Friedreich ataxia AR 11 62
GAN Giant axonal neuropathy AR 12 74
GARS Neuropathy, distal hereditary motor, Charcot-Marie-Tooth disease AD 14 35
GDAP1 Charcot-Marie-Tooth disease AD/AR 35 89
GJB1 Charcot-Marie-Tooth neuropathy XL 78 459
GNB4 Charcot-Marie-Tooth disease AD 2 4
GNE Inclusion body myopathy, Nonaka myopathy, Sialuria AD/AR 50 200
HADHB Trifunctional protein deficiency AR 17 57
HARS Usher syndrome AR 5 9
HINT1 Axonal neuropathy with neuromyotonia AR 7 12
HK1 Hemolytic anemia, nonspherocytic, due to hexokinase deficiency AD/AR 9 7
HSPB1 Neuropathy, distal hereditary motor, Charcot-Marie-Tooth disease AD 16 40
HSPB8 Charcot-Marie-Tooth disease, Distal hereditary motor neuronopathy AD 3 9
IGHMBP2 Spinal muscular atrophy, distal, Charcot-Marie-Tooth disease AR 36 125
INF2 Glomerulosclerosis, Charcot-Marie-Tooth disease AD 11 59
KARS Charcot-Marie-Tooth disease AR 7 20
KIF1A Spastic paraplegia, Neuropathy, hereditary sensory, Mental retardation AD/AR 52 35
KIF1B Pheochromocytoma, Neuroblastoma AD 7 10
KIF5A Spastic paraplegia AD 16 38
LDB3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 9 12
LITAF Charcot-Marie-Tooth disease AD 10 18
LMNA Heart-hand syndrome, Slovenian, Limb-girdle muscular dystrophy, Muscular dystrophy, congenital, LMNA-related, Lipodystrophy (Dunnigan), Emery-Dreiffus muscular dystrophy, Malouf syndrome, Dilated cardiomyopathy (DCM), Mandibuloacral dysplasia type A, Progeria Hutchinson-Gilford type AD/AR 211 513
LRSAM1 Charcot-Marie-Tooth disease AD/AR 10 12
MARS Interstitial lung and liver disease, Charcot-Marie-Tooth disease AD/AR 7 11
MED25 Basel-Vanagait-Smirin-Yosef syndrome, Charcot-Marie-Tooth disease AR 3 4
MFN2 Hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease AD/AR 52 218
MPZ Neuropathy, Roussy-Levy syndrome, Dejerine-Sottas disease, Charcot-Marie-Tooth disease AD 86 235
MTMR2 Charcot-Marie-Tooth disease AR 8 23
MYOT Myopathy, myofibrillar AD 8 16
NDRG1 Charcot-Marie-Tooth disease AR 6 5
NEFL Charcot-Marie-Tooth disease AD 23 36
NGF Neuropathy, hereditary sensory and autonomic AR 2 5
NTRK1 Insensitivity to pain, congenital, with anhidrosis AR 26 105
PDK3 Charcot-Marie-Tooth disease XL 1 2
PLEKHG5 Spinal muscular atrophy, Charcot-Marie-Tooth disease AR 9 8
PMP22 Neuropathy, inflammatory demyelinating, Roussy-Levy syndrome, Dejerine-Sottas disease, Neuropathy, hereditary, with liability to pressurve palsies, Charcot-Marie-Tooth disease AD/AR 42 159
POLG POLG-related ataxia neuropathy spectrum disorders, Sensory ataxia, dysarthria, and ophthalmoparesis, Alpers syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 92 274
PRPS1* Deafness, Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome XL 22 27
PRX Dejerine-Sottas disease, Charcot-Marie-Tooth disease AR 18 53
RAB7A Charcot-Marie-Tooth disease AD 5 7
REEP1 Spastic paraplegia, Distal hereditary motor neuronopathy AD 14 57
SACS Spastic ataxia, Charlevoix-Saguenay AR 116 234
SBF1 Charcot-Marie-Tooth disease AR 4 10
SBF2 Charcot-Marie-Tooth disease AR 15 19
SCN9A Paroxysmal extreme pain disorder AD/AR 41 104
SETX Ataxia with oculomotor apraxia, Amyotrophic lateral sclerosis, juvenile, Spinocerebellar ataxia AD/AR 27 190
SH3TC2 Mononeuropathy of the median nerve, Charcot-Marie-Tooth disease AR 42 80
SLC12A6 Agenesis of the corpus callosum with peripheral neuropathy (Andermann syndrome) AR 30 17
SMAD3 Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndrome AD 35 53
SPG11 Spastic paraplegia, Amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease AR 129 254
SPTLC1* Neuropathy, hereditary sensory and autonomic AD 7 10
SPTLC2 Hereditary sensory and autonomic neuropathy AD 4 14
SURF1 Leigh syndrome, Charcot-Marie-Tooth disease AR 43 95
TFG Spastic paraplegia, Hereditary motor and sensory neuropathy, proximal AR 4 7
TRIM2 Charcot-Marie-Tooth disease AR 3 8
TRPV4 Metatropic dysplasia, Spondyloepiphyseal dysplasia Maroteaux type, Parastremmatic dwarfism, Hereditary motor and sensory neuropathy, Spondylometaphyseal dysplasia Kozlowski type, Spinal muscular atrophy, Charcot-Marie-Tooth disease, Brachyolmia (autosomal dominant type), Familial Digital arthropathy with brachydactyly AD 58 74
TYMP Mitochondrial DNA depletion syndrome AR 85 94
VCP Amyotrophic lateral sclerosis, Inclusion body myopathy with early-onset Paget disease, Charcot-Marie-Tooth disease AD 16 54
WNK1 Neuropathy, hereditary sensory and autonomic, Pseudohypoaldosteronism AD/AR 15 7
YARS Charcot-Marie-Tooth disease AD 6 10

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
AIFM1 ChrX:129299753 c.-123G>C NM_004208.3 rs724160014
CTDP1 Chr18:77470825 c.863+389C>T NM_004715.4 rs113994102
GJB1 ChrX:70443099 c.-103C>T NM_000166.5 rs863224971
GJB1 ChrX:70443540 c.-16-2A>G NM_001097642.2
HK1 Chr10:71038467 c.-390-3818G>C NM_033500.2 rs397514654
HK1 Chr10:71038447 c.-390-3838G>C NM_033500.2 rs797044964
LMNA Chr1:156100609 c.513+45T>G NM_170707.3
NTRK1 Chr1:156843392 c.851-33T>A NM_002529.3 rs80356674

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Blueprint Genetics offers a comprehensive Charcot-Marie-Tooth Neuropathy Panel that covers classical genes associated with Charcot-Marie-Tooth neuropathy. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Charcot-Marie-Tooth Neuropathy Panel

ICD-10 Disease
G60.0 Charcot-Marie-Tooth neuropathy

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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