Charcot-Marie-Tooth Neuropathy Panel

Last modified: Jun 12, 2018

Summary

  • Is a 98 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of Charcot-Marie-Tooth neuropathy.

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

4 weeks

Number of genes

98

Test code

NE1301

Panel size

Large

CPT codes

DEL/DUP 81324
SEQ 81325
SEQ 81405
SEQ 81406

Summary

The Blueprint Genetics Charcot-Marie-Tooth Neuropathy Panel (test code NE1301):

  • Is a 98 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) when ordering the Charcot-Marie-Tooth Neuropathy Panel

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

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • 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.

Charcot-Marie-Tooth (CMT) neuropathy, also known as hereditary motor/sensory neuropathy (HMSN) is the most common genetic cause of neuropathy. Prevalence is estimated to be 1:3,300. CMT is characterized by broad genetic heterogeneity and can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. 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 of life, 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 demyelinating and axonal forms.

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 6 16
AIFM1 Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome XL 27 29
AMACR Alpha-methylacyl-CoA racemase deficiency, Bile acid synthesis defect AR 3 8
ARHGEF10 Slowed nerve conduction velocity AD 3 11
ATAD3A* Harel-Yoon syndrome AD/AR 4 15
ATL1 Spastic paraplegia, Neuropathy, hereditary sensory AD 28 79
ATL3 Neuropathy, hereditary sensory AD 1 4
ATP7A Menkes disease, Occipital horn syndrome, Spinal muscular atrophy, distal, X-linked 3 XL 113 354
BAG3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 36 60
BSCL2 Lipodystrophy, congenital generalized, Encephalopathy, progressive, Neuropathy, distal hereditary motor, type VA, Charcot-Marie-Tooth disease type 2, Silver syndrome, Silver spastic paraplegia syndrome, Spastic paraplegia 17 AR 32 47
C12ORF65 Spastic paraplegia, Combined oxidative phosphorylation deficiency AR 10 11
CCT5 Neuropathy, hereditary sensory, with spastic paraplegia AR 1 1
CHCHD10 Myopathy, isolated mitochondrial, Frontotemporal dementia and/or amyotrophic lateral sclerosis 2, Spinal muscular atrophy, Jokela type AD 4 20
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 Giant axonal neuropathy 2, autosomal dominant AD 1 1
DCTN1 Perry syndrome, Neuropathy, distal hereditary motor AD 10 45
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 27 46
DNMT1 Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy AD 9 19
DST Neuropathy, hereditary sensory and autonomic AR 9 7
DYNC1H1 Spinal muscular atrophy, Charcot-Marie-Tooth disease, Mental retardation AD 57 64
EGR2 Neuropathy, Dejerine-Sottas disease, Charcot-Marie-Tooth disease AD/AR 13 21
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 18 27
FIG4 Amyotrophic lateral sclerosis, Polymicrogyria, bilateral occipital, Yunis-Varon syndrome, Charcot-Marie-Tooth disease AD/AR 29 60
FXN* Friedreich ataxia AR 12 63
GAN Giant axonal neuropathy AR 16 74
GARS Neuropathy, distal hereditary motor, Charcot-Marie-Tooth disease AD 18 37
GDAP1 Charcot-Marie-Tooth disease AD/AR 36 95
GJB1 Charcot-Marie-Tooth neuropathy XL 91 472
GNB4 Charcot-Marie-Tooth disease AD 3 5
GNE Inclusion body myopathy, Nonaka myopathy, Sialuria AD/AR 58 201
HADHB Trifunctional protein deficiency AR 18 60
HARS* Usher syndrome, Charcot-Marie-Tooth disease, axonal, type 2W AR 4 9
HINT1 Axonal neuropathy with neuromyotonia AR 7 12
HK1 Hemolytic anemia, nonspherocytic, due to hexokinase deficiency, Retinitis pigmentosa 79, Neuropathy, motor and sensory, Russe type (Charcot-Marie-Tooth disease type 4G) AD/AR 9 7
HSPB1 Neuropathy, distal hereditary motor, Charcot-Marie-Tooth disease AD 19 43
HSPB8 Charcot-Marie-Tooth disease, Distal hereditary motor neuronopathy AD 3 10
IGHMBP2 Spinal muscular atrophy, distal, Charcot-Marie-Tooth disease AR 43 126
IKBKAP Dysautonomia, familial, Hereditary sensory and autonomic neuropathy AR 10 4
INF2 Glomerulosclerosis, Charcot-Marie-Tooth disease AD 14 63
KARS Charcot-Marie-Tooth disease AR 7 23
KIF1A Spastic paraplegia, Neuropathy, hereditary sensory, Mental retardation AD/AR 58 39
KIF1B Pheochromocytoma, Neuroblastoma, Charcot-Marie-Tooth disease, type 2A1 AD 7 10
KIF5A Spastic paraplegia AD 18 40
LDB3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 9 14
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 231 553
LRSAM1 Charcot-Marie-Tooth disease AD/AR 10 13
MARS Interstitial lung and liver disease, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease, axonal, type 2U AD/AR 8 11
MCM3AP Charcot-Marie-Tooth neuropathy AR 19
MED25 Basel-Vanagait-Smirin-Yosef syndrome, Charcot-Marie-Tooth disease AR 4 5
MFN2 Hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease AD/AR 59 220
MME Spinocerebellar ataxia 43, Charcot-Marie-Tooth disease, axonal, type 2T AD/AR 14 19
MPZ Neuropathy, Roussy-Levy syndrome, Dejerine-Sottas disease, Charcot-Marie-Tooth disease AD 99 240
MTMR2 Charcot-Marie-Tooth disease AR 8 23
MYOT Myopathy, myofibrillar, Muscular dystrophy, limb-girdle, 1A, Myopathy, spheroid body AD 7 16
NDRG1 Charcot-Marie-Tooth disease AR 6 8
NEFH* Charcot-Marie-Tooth disease, axonal, type 2CC AD/AR 3 18
NEFL Charcot-Marie-Tooth disease AD 23 39
NGF Neuropathy, hereditary sensory and autonomic AR 2 6
NTRK1 Insensitivity to pain, congenital, with anhidrosis, Medullary thyroid carcinoma, familial AR 30 108
PDK3 Charcot-Marie-Tooth disease XL 1 3
PLEKHG5 Spinal muscular atrophy, Charcot-Marie-Tooth disease AR 13 8
PMP22 Neuropathy, inflammatory demyelinating, Roussy-Levy syndrome, Dejerine-Sottas disease, Neuropathy, hereditary, with liability to pressurve palsies, Charcot-Marie-Tooth disease AD/AR 44 164
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 90 280
PRDM12 Neuropathy, hereditary sensory and autonomic, type VIII AR 7 11
PRPS1* Deafness, Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome, Charcot-Marie-Tooth disease, X-linked recessive, 5, Nonsyndromic sensorineural deafness, 2, X-linked XL 27 31
PRX Dejerine-Sottas disease, Charcot-Marie-Tooth disease AR 21 53
RAB7A Charcot-Marie-Tooth disease AD 5 7
REEP1 Spastic paraplegia, Distal hereditary motor neuronopathy AD 16 59
SACS Spastic ataxia, Charlevoix-Saguenay AR 131 239
SBF1 Charcot-Marie-Tooth disease AR 5 10
SBF2 Charcot-Marie-Tooth disease AR 17 19
SCN9A Paroxysmal extreme pain disorder, Small fiber neuropathy, Erythermalgia, primary, Geberalized epilepsy with febrile seizures plus, type 7, Insensitivity to pain, congenital, autosomal recessive AD/AR 51 116
SCN11A Episodic pain syndrome, familial, 3, Neuropathy, hereditary sensory and autonomic, type VII AD 8 18
SEPT9 Amyotrophy, hereditary neuralgic AD 4 11
SETX Ataxia with oculomotor apraxia, Amyotrophic lateral sclerosis, juvenile, Spinocerebellar ataxia AD/AR 35 194
SH3TC2 Mononeuropathy of the median nerve, Charcot-Marie-Tooth disease AR 51 80
SLC12A6 Agenesis of the corpus callosum with peripheral neuropathy (Andermann syndrome) AR 31 17
SLC25A46 Neuropathy, hereditary motor and sensory, type VIB AR 12 13
SMAD3 Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndrome AD 43 55
SPG11 Spastic paraplegia, Amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease AR 146 262
SPTLC1* Neuropathy, hereditary sensory and autonomic AD 8 11
SPTLC2 Hereditary sensory and autonomic neuropathy AD 5 14
SURF1 Leigh syndrome, Charcot-Marie-Tooth disease AR 49 98
TFG Spastic paraplegia, Hereditary motor and sensory neuropathy, proximal AR 4 7
TRIM2 Charcot-Marie-Tooth disease AR 4 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 60 76
TTR Dystransthyretinemic hyperthyroxinemia, Amyloidosis, hereditary, transthyretin-related AD 49 146
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 18 57
WNK1 Neuropathy, hereditary sensory and autonomic, Pseudohypoaldosteronism AD/AR 15 7
YARS Charcot-Marie-Tooth disease AD 6 11
ZFYVE26 Spastic paraplegia 15 AR 26 38

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
AIFM1 ChrX:129299753 c.-123G>C NM_004208.3 rs724160014
ATP7A ChrX:77279056 c.2916+2480T>G NM_000052.5
ATP7A ChrX:77287843 c.3294+763C>G NM_000052.5
BSCL2 Chr11:62470032 c.405-11A>G NM_001122955.3
CTDP1 Chr18:77470825 c.863+389C>T NM_004715.4 rs113994102
GJB1 ChrX:70444424 c.*15C>T NM_001097642.2
GJB1 ChrX:70443099 c.-103C>T NM_000166.5 rs863224971
GJB1 ChrX:70443541 c.-16-1G>A NM_001097642.2
GJB1 ChrX:70443540 c.-16-2A>G NM_001097642.2
GJB1 ChrX:70443539 c.-16-3C>G NM_001097642.2
GJB1 ChrX:70443031 c.-16-511G>C NM_001097642.2
GJB1 ChrX:70443029 c.-16-513T>C/G NM_001097642.2
GJB1 ChrX:70443018 c.-16-524C>G NM_001097642.2
GJB1 ChrX:70443186 c.-17+1G>T NM_000166.5
GJB1 ChrX:70443187 c.-17+2T>C NM_000166.5
GJB1 ChrX:70443185 c.-17G>A NM_000166.5
HADHB Chr2:26500642 c.442+614A>G NM_000183.2
HK1 Chr10:71038467 c.-390-3818G>C NM_033500.2 rs397514654
HK1 Chr10:71038447 c.-390-3838G>C NM_033500.2 rs797044964
HK1 Chr10:71075518 c.27+14901A>G NM_033500.2 rs187500777
HSPB1 Chr7:75931813 c.-217T>C NM_001540.3 rs545738637
LMNA Chr1:156107037 c.1608+14G>A NM_170707.3
LMNA Chr1:156107433 c.1609-12T>G NM_170707.3 rs267607582
LMNA Chr1:156100609 c.513+45T>G NM_170707.3
LMNA Chr1:156105681 c.937-11C>G NM_170707.3 rs267607645
NTRK1 Chr1:156851238 c.2206-11G>A NM_002529.3
NTRK1 Chr1:156851237 c.2206-12C>A NM_002529.3
NTRK1 Chr1:156843392 c.851-33T>A NM_002529.3 rs80356674
PMP22 Chr17:15162523 c.79-13T>A NM_000304.3
SH3TC2 Chr5:148406329 c.2873-14T>A NM_024577.3
SURF1 Chr9:136220806 c.324-11T>G NM_003172.3 rs375398247
VCP Chr9:35072710 c.-360G>C NM_007126.3

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

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.

The Blueprint Genetics Charcot-Marie-Tooth neuropathy panel covers classical genes associated with Charcot-Marie-Tooth neuropathy. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics' Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient's phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. 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. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.