- 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.
The Blueprint Genetics Charcot-Marie-Tooth Neuropathy Panel (test code NE1301):
Commonly used ICD-10 code(s) when ordering the Charcot-Marie-Tooth Neuropathy Panel
- Blood (min. 1ml) in an EDTA tube
- Extracted DNA, min. 2 μg in TE buffer or equivalent
- Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)
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. Read more about our sample requirements here.
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
|AARS||Epileptic encephalopathy, early infantile, Charcot-Marie-Tooth disease||AD/AR||9||16|
|AIFM1||Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome||XL||27||31|
|AMACR||Alpha-methylacyl-CoA racemase deficiency, Bile acid synthesis defect||AR||3||8|
|ARHGEF10||Slowed nerve conduction velocity||AD||4||12|
|ATL1||Spastic paraplegia, Neuropathy, hereditary sensory||AD||29||84|
|ATL3||Neuropathy, hereditary sensory||AD||1||4|
|ATP7A||Menkes disease, Occipital horn syndrome, Spinal muscular atrophy, distal, X-linked 3||XL||116||354|
|BAG3||Dilated cardiomyopathy (DCM), Myopathy, myofibrillar||AD||39||62|
|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||34||50|
|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||26|
|COX10*||Leigh syndrome, Mitochondrial complex IV deficiency||AR||52||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||52|
|DHTKD1||2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease||AD/AR||11||18|
|DNM2||Myopathy, Lethal akinesia and musculoskeletal abnormalities, with brain and retinal hemorrhages, Charcot-Marie-Tooth disease||AD/AR||28||47|
|DNMT1||Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy||AD||9||20|
|DST||Neuropathy, hereditary sensory and autonomic||AR||13||7|
|DYNC1H1||Spinal muscular atrophy, Charcot-Marie-Tooth disease, Mental retardation||AD||60||71|
|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||22|
|FIG4||Amyotrophic lateral sclerosis, Polymicrogyria, bilateral occipital, Yunis-Varon syndrome, Charcot-Marie-Tooth disease||AD/AR||34||69|
|GAN||Giant axonal neuropathy||AR||18||76|
|GARS||Neuropathy, distal hereditary motor, Charcot-Marie-Tooth disease||AD||19||38|
|GNE||Inclusion body myopathy, Nonaka myopathy, Sialuria||AD/AR||78||214|
|HADHB||Trifunctional protein deficiency||AR||20||65|
|HARS*||Usher syndrome, Charcot-Marie-Tooth disease, axonal, type 2W||AR||6||12|
|HINT1||Axonal neuropathy with neuromyotonia||AR||11||15|
|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||27||44|
|HSPB8||Charcot-Marie-Tooth disease, Distal hereditary motor neuronopathy||AD||6||9|
|IGHMBP2||Spinal muscular atrophy, distal, Charcot-Marie-Tooth disease||AR||52||128|
|IKBKAP||Dysautonomia, familial, Hereditary sensory and autonomic neuropathy||AR||47||6|
|INF2||Glomerulosclerosis, Charcot-Marie-Tooth disease||AD||20||67|
|KIF1A||Spastic paraplegia, Neuropathy, hereditary sensory, Mental retardation||AD/AR||63||42|
|KIF1B||Pheochromocytoma, Neuroblastoma, Charcot-Marie-Tooth disease, type 2A1||AD||7||12|
|LDB3||Dilated cardiomyopathy (DCM), Myopathy, myofibrillar||AD||9||14|
|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||250||564|
|MARS||Interstitial lung and liver disease, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease, axonal, type 2U||AD/AR||9||13|
|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||70||223|
|MME||Spinocerebellar ataxia 43, Charcot-Marie-Tooth disease, axonal, type 2T||AD/AR||14||21|
|MPZ||Neuropathy, Roussy-Levy syndrome, Dejerine-Sottas disease, Charcot-Marie-Tooth disease||AD||108||241|
|MYOT||Myopathy, myofibrillar, Muscular dystrophy, limb-girdle, 1A, Myopathy, spheroid body||AD||6||16|
|NEFH*||Charcot-Marie-Tooth disease, axonal, type 2CC||AD/AR||4||21|
|NGF||Neuropathy, hereditary sensory and autonomic||AR||2||6|
|NTRK1||Insensitivity to pain, congenital, with anhidrosis, Medullary thyroid carcinoma, familial||AR||38||123|
|PLEKHG5||Spinal muscular atrophy, Charcot-Marie-Tooth disease||AR||16||8|
|PMP22||Neuropathy, inflammatory demyelinating, Roussy-Levy syndrome, Dejerine-Sottas disease, Neuropathy, hereditary, with liability to pressurve palsies, Charcot-Marie-Tooth disease||AD/AR||49||165|
|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||89||290|
|PRDM12||Neuropathy, hereditary sensory and autonomic, type VIII||AR||7||11|
|PRPS1*||Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome, Charcot-Marie-Tooth disease, X-linked recessive, 5, Deafness, X-linked 1||XL||27||32|
|PRX||Dejerine-Sottas disease, Charcot-Marie-Tooth disease||AR||26||55|
|REEP1||Spastic paraplegia, Distal hereditary motor neuronopathy||AD||16||60|
|SACS||Spastic ataxia, Charlevoix-Saguenay||AR||254||262|
|SCN11A||Episodic pain syndrome, familial, 3, Neuropathy, hereditary sensory and autonomic, type VII||AD||8||20|
|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||61||125|
|SEPT9||Amyotrophy, hereditary neuralgic||AD||4||11|
|SETX||Ataxia with oculomotor apraxia, Amyotrophic lateral sclerosis, juvenile, Spinocerebellar ataxia||AD/AR||36||210|
|SH3TC2||Mononeuropathy of the median nerve, Charcot-Marie-Tooth disease||AR||63||89|
|SLC12A6||Agenesis of the corpus callosum with peripheral neuropathy (Andermann syndrome)||AD/AR||43||19|
|SLC25A46||Neuropathy, hereditary motor and sensory, type VIB||AR||14||17|
|SMAD3||Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndrome||AD||48||82|
|SPG11||Spastic paraplegia, Amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease||AR||162||274|
|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||50||101|
|TFG||Spastic paraplegia, Hereditary motor and sensory neuropathy, proximal||AR||4||7|
|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||61||78|
|TTR||Dystransthyretinemic hyperthyroxinemia, Amyloidosis, hereditary, transthyretin-related||AD||52||148|
|TYMP||Mitochondrial DNA depletion syndrome||AR||84||94|
|VCP||Amyotrophic lateral sclerosis, Inclusion body myopathy with early-onset Paget disease, Charcot-Marie-Tooth disease||AD||17||61|
|WNK1||Neuropathy, hereditary sensory and autonomic, Pseudohypoaldosteronism||AD/AR||14||9|
|ZFYVE26||Spastic paraplegia 15||AR||63||39|
* 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 Charcot-Marie-Tooth Neuropathy Panel
|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
- 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
Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).
- 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).
- 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%|
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.
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 is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance
(VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a 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 (Plus analysis only).
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.