Coverage Policy Manual
Policy #: 2013022
Category: Laboratory
Initiated: July 2013
Last Review: February 2025
  Genetic Test: Inherited Peripheral Neuropathies (Charcot Marie Tooth, HNPP)
Description:
Inherited peripheral neuropathies are a clinically and genetically heterogeneous group of disorders. The estimated prevalence in aggregate is 1 in 2500 persons, making inherited peripheral neuropathies the most common inherited neuromuscular disease (Burgunder, 2011).
 
Peripheral neuropathies can be subdivided into 2 major categories: primary axonopathies and primary myelinopathies, depending on which portion of the nerve fiber is affected. Further anatomic classification includes fiber type (e.g., motor vs sensory, large vs small), and gross distribution of the nerves affected (e.g., symmetry, length-dependency).
 
The inherited peripheral neuropathies are divided into the hereditary motor and sensory neuropathies, hereditary neuropathy with liability to pressure palsies, and other miscellaneous, rare types (e.g., hereditary brachial plexopathy, hereditary sensory, autonomic neuropathies). Other hereditary metabolic disorders, such as Friedreich ataxia, Refsum disease, and Krabbe disease, may be associated with motor and/or sensory neuropathies but typically have other predominating symptoms. This policy will focus on the hereditary motor and sensory neuropathies and HNPP.
 
A genetic etiology of a peripheral neuropathy is typically suggested by generalized polyneuropathy, family history, lack of positive sensory symptoms, early age of onset, symmetry, associated skeletal abnormalities, and very slowly progressive clinical course (Alport, 2012). A family history of at least 3 generations with details on health issues, the cause of death, and age at death should be collected.
 
Hereditary Motor and Sensory Neuropathies
Most inherited polyneuropathies were originally described clinically as variants of Charcot-Marie-Tooth (CMT) disease. The clinical phenotype of CMT is highly variable, ranging from minimal neurologic findings to the classic picture with pes cavus and “stork legs” to a severe polyneuropathy with respiratory failure (England, 2009). CMT disease is genetically heterogeneous, as well as clinically heterogeneous. Variants in more than 30 genes and more than 44 different genetic loci have been associated with inherited neuropathies (Saporta, 2011). In addition, different pathogenic variants in a single gene can lead to different inherited neuropathy phenotypes and different inheritance patterns. A 2016 cross-sectional study of 520 children and adolescents with CMT found variability in CMT-related symptoms across the 5 most commonly represented subtypes (Cornett, 2016).
 
CMT subtypes are characterized by variants in one of several myelin genes, which lead to abnormalities in myelin structure, function, or upkeep. There are 7 subtypes of CMT, with type 1 and 2 representing the most common hereditary peripheral neuropathies.
 
Most cases of CMT are autosomal dominant, although autosomal recessive and X-linked dominant forms exist. Most cases are CMT type 1 (approximately 40%-50% of all CMT cases, with 78%-80% of those due to PMP22 mutations) (Bird, 2015). CMT type 2 is associated with about 10% to 15% of CMT cases, with 20% of those due to MFN2 mutations.
 
A summary of the molecular genetics of CMT is outlined below.
 
Molecular Genetics of CMT Variants (Listed according to Locus, Gene, Protein Product) (Adapted from Bird, 2023)
 
CMT type 1
    • CMT1A. PMP22. Peripheral myelin protein 22. Prevalence: 50% of CMT1
    • CMT1B. MPZ. Myelin P0 protein. Prevalence: 25% of CMT1
    • CMT1C. LITAF. Lipopolysaccharide-induced tumor necrosis factor-a factor.
    • CMT1D. EGR2 Early growth response protein 2
    • CMT1E. PMP22 Peripheral myelin protein 22 (sequence changes)
    • CMT1F/2E. NEFL Neurofilament light polypeptide
    • CMT1G. PMP2. Peripheral myelin protein 2
 
CMT type 2
    • CMT2A1. KIF1B. Kinesin-like protein KIF1B
    • CMT2A2A/B. MFN2. Mitofusin-2.
    • CMT2B. RAB7A. Ras-related protein Rab-7
    • CMT2B1. LMNA. Lamin A/C
    • CMT2B2. PNKP
    • CMT2C. TRPV4. Transient receptor potential cation channel subfamily V member 4
    • CMT2D. GARS1. Glycyl-tRNA synthetase
    • CMT2F. HSPB1. Heat-shock protein beta-1
    • CMT2G. LRSAM1. E3 ubiquitin-protein ligase LRSAM1
    • CMT2H/2K. GDAP1. Ganglioside-induced differentiation-associated protein 1
    • CMT2I/2J. MPZ. Myelin P0 protein
    • CMT2L. HSPB8. Heat-shock protein beta-8
    • CMT2M. DNM2. Dynamin 2
    • CMT2N. AARS1. Alanyl-tRNA synthetase, cytoplasmic
    • CMT2O. DYNC1H1. Cytoplasmic dynein 1 heavy chain 1
    • CMT2P. LRSAM1. E3 ubiquitin-protein ligase LRSAM1
    • CMT2Q. DHTKD1. Dehydrogenase E1 and Transketolase Domain Containing 1
    • CMT2R. TRIM2. Tripartite Motif Containing 2
    • CMT2S. IGHMBP2. DNA-binding protein SMUBP-2
    • CMT2T. MME Membrane Metalloendopeptidase
    • CMT2U. MARS1. Methionine-tRNA ligase, cytoplasmic
    • CMT2V NAGLU . N-Acetyl-Alpha-Glucosaminidase
    • CMT2W. HARS1. Histidyl-TRNA Synthetase 1
    • CMT2X. SPG11. Spastic paraplegia 11
    • CMT2Y. VCP. Valosin Containing Protein
    • CMT2Z. MORC2. Microrchidia Family CW-Type Zinc Finger 2
 
CMT type 4
    • CMT4A. GDAP1. Ganglioside-induced differentiation-associated protein 1
    • CMT4B1. MTMR2. Myotubularin-related protein 2
    • CMT4B2. SBF2. Myotubularin-related protein 13
    • CMT4B3. SBF1. SET Binding Factor 1
    • CMT4C. SH3TC2. SH3 domain and tetratricopeptide repeats-containing protein 2
    • CMT4D. NDRG1. Protein NDRG1
    • CMT4E. EGR2. Early growth response protein 2
    • CMT4F. PRX. Periaxin
    • CMT4H. FGD4. FYVE, RhoGEF, and PH domain-containing protein 4
    • CMT4J. FIG4. Phosphatidylinositol 3, 5-biphosphate
 
X-linked CMT
    • CMTX3. Xq26. Unknown
    • CMTX4. AIFM1. Apoptosis-inducing factor 1
    • CMTX5. PRPS1. Ribose-phosphate pyrophosphokinase 1
    • CMTX6. PDK3. Pyruvate dehydrogenase kinase isoform 3
 
CMT Type 1
CMT1 is an autosomal dominant, demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. It is usually slowly progressive and often associated with pes cavus foot deformity, bilateral foot drop, and palpably enlarged nerves, especially the ulnar nerve at the olecranon groove and the greater auricular nerve. Affected people usually become symptomatic between age 5 and 25 years, and lifespan is not shortened. Less than 5% of people become wheelchair dependent. CMT1 is inherited in an autosomal dominant manner. The CMT1 subtypes (CMT 1A-E) are separated by molecular findings and are often clinically indistinguishable. CMT1A accounts for 70% to 80% of all CMT1, and about two-thirds of probands with CMT1A have inherited the disease-causing mutation and about one-third have CMT1A as the result of a de novo variant.
 
CMT1A involves duplication of the PMP22 gene. PMP22 encodes an integral membrane protein, peripheral membrane protein 22, which is a major component of myelin in the peripheral nervous system. The phenotypes associated with this disease arise because of abnormal PMP22 gene dosage effects (Stankiewicz, 2006). Two normal alleles represent the normal wild-type condition. Four normal alleles (as in the homozygous CMT1A duplication) results in the most severe phenotype, whereas 3 normal alleles (as in the heterozygous CMT1A duplication) cause a less severe phenotype (Bird, 1993).
 
CMT Type 2
CMT2 is a non-demyelinating (axonal) peripheral neuropathy characterized by distal muscle weakness and atrophy, mild sensory loss, and normal or near-normal nerve conduction velocities. Clinically, CMT2 is similar to CMT1, although typically less severe (Bird, 1993). The subtypes of CMT2 are similar clinically and distinguished only by molecular genetic findings. CMT2B1, CMT2B2, and CMT2H/K are inherited in an autosomal recessive manner; all other subtypes of CMT2 are inherited in an autosomal dominant manner. The most common subtype of CMT2 is CMT2A, which accounts for approximately 20% of CMT2 cases and is associated with mutations in the MFN2 gene.
 
X-Linked CMT
CMT X type 1 (CMTX1) is characterized by a moderate to severe motor and sensory neuropathy in affected males and mild to no symptoms in carrier females (Abrams, 2020). Sensorineural deafness and central nervous system symptoms also occur in some families. CMTX1 is inherited in an X-linked dominant manner. Molecular genetic testing of GJB1 (Cx32), which is available on a clinical basis, detects about 90% of cases of CMTX1.
 
CMT Type 4
CMT type 4 (CMT4) is a form of hereditary motor and sensory neuropathy that is inherited in an autosomal recessive fashion and occurs secondary to myelinopathy or axonopathy. It occurs more rarely than the other forms of CMT neuropathy, but some forms may be rapidly progressive and/or associated with severe weakness.
 
Hereditary Neuropathy With Liability to Pressure Palsies
The largest proportion of CMT1 cases are due to mutations in PMP22. In HNPP (also called tomaculous neuropathy), inadequate production of PMP22 causes nerves to be more susceptible to trauma or minor compression or entrapment. HNPP patients rarely present symptoms before the second or third decade of life. However, some have reported presentation as early as birth or as late as the seventh decade of life (Bird, 1993). The prevalence is estimated at 16 persons per 100,000 although some authors indicate a potential for underdiagnosis of the disease (Meretoza, 1997). An estimated 50% of carriers are asymptomatic and do not display abnormal neurologic findings on clinical examination (Celik, 2008). HNPP is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop and episodes of numbness, muscular weakness, atrophy, and palsies due to minor compression or trauma to the peripheral nerves. The disease is benign with complete recovery occurring within a period of days to months in most cases, although an estimated 15% of patients have residual weakness following an episode (Celik, 2008). Poor recovery usually involves a history of prolonged pressure on a nerve, but in these cases the remaining symptoms are typically mild.
 
PMP22 is the only gene in which a variant is known to cause HNPP. A large deletion occurs in approximately 80% of patients, and the remaining 20% of patients have single nucleotide variants (SNVs) and small deletions in the PMP22 gene. One normal allele (due to a 17p11.2 deletion) results in HNPP and a mild phenotype. SNVs in PMP22 have been associated with a variable spectrum of HNPP phenotypes ranging from mild symptoms to representing a more severe, CMT1-like syndrome (Taioli, 2011). Studies have also reported that the SNV frequency may vary considerably by ethnicity (Bissar-Tadmouri, 2000). About 10% to 15% of variant carriers remain clinically asymptomatic, suggesting incomplete penetrance (Dubourg, 2000).
 
Treatment
Currently there is no effective therapy to slow the progression of neuropathy for the inherited peripheral neuropathies. A 2015 systematic review of exercise therapies for CMT including 9 studies described in 11 articles reported significant improvements with functional activities and physiological adaptations with exercise (Sman, 2015). Supportive treatment, if necessary, is generally provided by a multidisciplinary team including neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Treatment choices are limited to physical therapy, use of orthotics, surgical treatment for skeletal or soft tissue abnormalities, and drug treatment for pain (Pareyson, 2009). Avoidance of obesity and drugs that are associated with nerve damage (i.e., vincristine, Taxol, cisplatin, isoniazid, and nitrofurantoin) is recommended in CMT patients (Bird, 2015).
 
Supportive treatment for HNPP can include transient bracing (e.g., wrist splint or ankle-foot orthosis) which may become permanent in some cases of foot drop (Bird, 2014). Prevention of HNPP manifestations can be accomplished by wearing protective padding (e.g., elbow or knee pads) to prevent trauma to nerves during activity. Some have reported that vincristine should also be avoided in HNPP patients (Bird, 1993; Bird, 2015). Ascorbic acid has been investigated as a treatment for CMT1A based on animal models, but a 2013 trial in humans did not demonstrate significant clinical benefit (Lewis, 2013). Attarian et al reported results of an exploratory phase 2 randomized, double-blind, placebo-controlled trial of PXT3003, a low-dose combination of 3 already approved compounds (baclofen, naltrexone, sorbitol) in 80 adults with CMT1A (Attarian, 2014). The study demonstrated the safety and tolerability of the drug. Mandel et al included this randomized controlled trial and 3 other trials (1 of ascorbic acid, 2 of PXT3003) in a meta-analysis (Mandel, 2015).
 
Available Molecular Genetic Testing
Multiple laboratories offer individual variant testing for genes involved in hereditary sensory and motor neuropathies, which would typically involve sequencing analysis via Sanger sequencing or next-generation sequencing (NGS) followed by deletion/duplication analysis (i.e., with array comparative genomic hybridization [CGH]) to detect large deletions or duplications. For the detection of mutations in MFN2, whole gene or select exome sequence analysis is typically used to identify SNVs, in addition to or followed by deletion or duplication analysis for the detection of large deletions or duplications.
 
Aretz et al reported a general estimation of the clinical sensitivity of CMT variant testing for hereditary motor and sensory neuropathy and HNPP using a variety of analytic methods (multiplex ligation-dependent probe amplification, multiplex amplicon quantification, quantitative polymerase chain reaction, Southern blot, fluorescence in-situ hybridization, pulsed-field gel electrophoresis, denaturing high-performance liquid chromatography, high-resolution melting, restriction analysis, direct sequencing) (Aretz, 2010). The clinical sensitivity (i.e., the proportion of positive tests if the disease is present) for the detection of deletions/duplications or mutations to PMP22 was about 50% and 1%, respectively, for single nucleotide variants. The clinical specificity (i.e., the proportion of negative tests if the disease is not present) was nearly 100%
 
A number of genetic panel tests for the assessment of peripheral neuropathies are commercially available. For example, GeneDx (Gaithersburg, MD) offers an Axonal CMT panel, which uses NGS and exon array CGH. The genes tested include the following: AARS, AIFM1, BSCL2, DNAJB2, DNM2, DYNC1H1, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HINT1, HSPB1, HSPB8, IGHMBP2, INF2, KIF5A, LMNA, LRSAM1, MFN2, MME, MORC2, MPZ, NEFL, PLEKHG5, PRPS1, RAB7A, SLC12A6, TRIM2, TRPV4, and YARS (GeneDx, 2023). InterGenetics (Athens, Greece) offers a NGS panel for neuropathy that includes 42 genes involved in CMT, along with other hereditary neuropathies. Fulgent Clinical Diagnostics Lab offers a broader NGS panel for CMT that includes 48 genes associated with CMT and other neuropathies and myopathies.
 
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Genetic testing for the diagnosis of inherited peripheral neuropathies is available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this.
 
Coding
 
CPT Tier 2 code 81403 includes the following test mentioned above –
 
GJB1 (gap junction protein, beta 1) (e.g., Charcot-Marie-Tooth X-linked), full gene sequence
 
CPT Tier 2 code 81404 includes the following tests mentioned above –
 
EGR2 (early growth response 2) (e.g., Charcot-Marie-Tooth), full gene sequence
HSPB1 (heat shock 27kDa protein 1) (e.g., Charcot-Marie-Tooth disease), full gene sequence
LITAF (lipopolysaccharide-induced TNF factor) (e.g., Charcot-Marie-Tooth), full gene sequence
 
CPT Tier 2 code 81405 includes the following tests mentioned above –
 
GDAP1 (ganglioside-induced differentiation-associated protein 1) (e.g., Charcot-Marie-Tooth disease), full
gene sequence.
MPZ (myelin protein zero) (e.g., Charcot-Marie-Tooth), full gene sequence
NEFL (neurofilament, light polypeptide) (e.g., Charcot-Marie-Tooth), full gene sequence
PRX (periaxin) (e.g., Charcot-Marie-Tooth disease), full gene sequence
RAB7A (RAB7A, member RAS oncogene family) (e.g., Charcot-Marie-Tooth disease), full gene sequence.
 
CPT Tier 2 code 81406 includes the following tests mentioned above –
 
FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae]) (e.g., Charcot-Marie-
Tooth disease), full gene sequence
GARS (glycyl-tRNA synthetase) (e.g., Charcot-Marie-Tooth disease), full gene sequence
LMNA (lamin A/C) (e.g., Emery-Dreifuss muscular dystrophy [EDMD1, 2 and 3] limb-girdle muscular
dystrophy [LGMD] type 1B, dilated cardiomyopathy [CMD1A], familial partial lipodystrophy [FPLD2]), full gene sequence
MFN2 (mitofusin 2) (e.g., Charcot-Marie-Tooth disease), full gene sequence.
SH3TC2 (SH3 domain and tetratricopeptide repeats 2) (e.g., Charcot-Marie-Tooth disease), full gene
Sequence
 
For the other genes listed above, there is no specific CPT listing of the test and the unlisted molecular pathology code 81479 would be reported.
Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing to confirm a clinical diagnosis of an inherited peripheral neuropathy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, genetic testing to confirm a clinical diagnosis of an inherited peripheral neuropathy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for an inherited peripheral neuropathy for all other indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, genetic testing for an inherited peripheral neuropathy for all other indications is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Validation of the clinical use of any genetic test focuses on 3 main principles: 1) analytic validity of the test, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; 2) clinical validity of the test, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and 3) clinical utility of the test, i.e., how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
 
Most of the published data available for analytic and clinical validity of genetic testing for the inherited peripheral neuropathies are for duplications and deletions in the PMP22 gene in the diagnosis of Charcot-Marie-Tooth (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively.
 
Analytic validity
A variety of methods, in addition to fluorescence in-situ hybridization (FISH), can be used for deletion/duplication analysis targeted specifically at PMP22, including quantitative polymerase chain reaction (qPCR), multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA), with high agreement between testing methods.
 
Analytic performance of several molecular analytic methods was presented in a review by Aretz et al (Aretz, 2010). The reported analytic sensitivity and specificity were given as almost 100% (tests considered included MLPA, qPCR, FISH, and direct sequencing). Further evidence is provided by another review where segregation studies followed by several prospective cohort studies have also documented that currently available genetic testing results for CMT are unequivocal for diagnosis of established pathogenic mutations, providing a specificity of 100% (i.e., no false positives) and high sensitivity (England, 2009).
 
Clinical validity
The clinical sensitivity of the diagnostic test for CMT and HNPP can be dependent on variable factors such as the age or family history of the patient. A general estimation of the clinical sensitivity was presented in a report by Aretz et al. on hereditary motor and sensory neuropathy and HNPP with a variety of analytic methods (MLPA, multiplex amplicon quantification [MAQ], qPCR, Southern blot, FISH, PFGE, dHPLC, high-resolution melting, restriction analysis and direct sequencing) (Aretz, 2010). The clinical sensitivity (i.e., proportion of positive tests if the disease is present) for the detection of deletions/duplications to PMP22 was about 50% and 1% for point mutations. The clinical specificity (i.e., proportion of negative tests if the disease is not present) was nearly 100%.
 
An evidence-based review by England and colleagues on the role of laboratory and genetic tests in the evaluation of distal symmetric polyneuropathies concluded that genetic testing is established as useful for the accurate diagnosis and classification of hereditary polyneuropathies in patients with a cryptogenic polyneuropathy who exhibit a classical hereditary neuropathy phenotype (England, 2009). Six studies included in the review showed that when the test for CMT1A duplication is restricted to patients with clinically probable CMT1 (i.e., autosomal dominant, primary demyelinating polyneuropathy), the yield is 54-80% as compared to testing a cohort of patients suspected of having any variety of hereditary peripheral neuropathy where the yield is only 25-59% (average of 43%).
 
Few genotype-phenotype correlations for CMT type 2 are known. Considerable variability of phenotype has been observed within families with CMT2A (Bird, 1993).
 
Clinical utility
The clinical utility of genetic testing for the hereditary peripheral neuropathies depends on how the results can be used to improve patient management. Published data for the clinical utility of genetic testing for the inherited peripheral neuropathies is lacking.
 
In a discussion of the clinical utility of the molecular diagnostic methods for these neuropathies, Aretz et al. suggest that the avoidance of any unnecessary therapy due to an undefined diagnosis, sparing other family members from testing, and avoidance of certain risk factors (e.g., obesity or certain occupations and activities) are potential benefits (Aretz, 2010).
 
The likelihood that genetic testing for this condition will alter patient management is low. Because the diagnosis of an inherited peripheral neuropathy can generally be made clinically and the inherited peripheral neuropathies have no specific therapy, the incremental benefit of a genetic confirmation of these disorders is not known.
 
Summary
The inherited peripheral neuropathies are a heterogeneous group of diseases which may be inherited in an autosomal dominant, autosomal recessive or X-linked dominant manner. These diseases can generally be diagnosed based on clinical presentation, nerve conduction studies and family history.
 
Genetic testing for most of the inherited peripheral neuropathies is commercially available. The analytic validity of mutation testing for these diseases is high. The specificity has also been reported to be high, with variable sensitivity.
 
However, the clinical utility of genetic testing to confirm a diagnosis in a patient with a clinical diagnosis of an inherited peripheral neuropathy is unknown.
 
Practice Guidelines and Position Statements
The American Academy of Neurology (AAN) published an evidence-based, tiered approach (England, 2009) for the evaluation of distal symmetric polyneuropathy, and for suspected hereditary neuropathies, which concluded that:
 
    • genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies (level A classification of recommendations- established as effective, ineffective, or harmful for the given condition in the specified population)
 
    • genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (level C- possibly effective, ineffective, or harmful for the given condition in the specified population)
 
    • initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1) and MFN2 screening
 
    • there is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (level U-data inadequate or conflicting; given current knowledge)
 
The American Academy of Family Physicians (AAFP) recommends genetic testing in a patient with suspected peripheral neuropathy, if basic blood tests are negative, electrodiagnostic studies suggest an axonal etiology and diseases such as diabetes, toxic medications, thyroid disease and vasculitides can be ruled out (Azhary, 2010).
 
2014 Update
A literature search conducted through June 2014 did not identify any new information that would prompt a change in the coverage statement.
 
Saporta et al reported results from genetic testing of 1024 patients with clinically suspected CMT who were evaluated at a single institution’s CMT clinic from 1997 to 2009 (Saporta, 2011). Patients who were included were considered to have CMT if they had a sensorimotor peripheral neuropathy and a family history of a similar condition. Patients without a family history of neuropathy were considered to have CMT if their medical history, neurophysiological testing, and neurologic examination were typical for CMT1, CMT2, CMTX, or CMT4. Seven hundred eighty-seven patients were diagnosed with CMT; of those, 527 (67%) had a specific genetic diagnosis as a result of their visit. Genetic testing decisions were left up to the treating clinician, and the authors note that decisions about which genes to test changed over the course of the period included in the study. Most (98.2%) of those with clinically-diagnosed CMT1 had a genetic diagnosis, and of all of the patients with a genetic diagnosis, most (80.8%) had clinically-diagnosed CMT1. The authors characterize several clinical phenotypes of CMT based on clinical presentation and physiologic testing.
 
2015 Update
A literature search conducted through June 2014 did not reveal any literature supporting the clinical utility genetic testing for the hereditary peripheral neuropathies. Several studies assessing the clinical validity of the testing were identified but do not prompt a change in the coverage statement.  
 
In 2015, Rudnik-Schoneborn et al described clinical features and genetic results from 1206 index patients and 124 affected relatives who underwent testing for CMT neuropathy at a single laboratory over an 11 year period from 2001 to 2012 (Rudnik-Schoneborn, 2015). Patients were categorized on the base of electroneurographic findings, clinical history, and inheritance pattern into CMT1, CMT2, or CMTX, or HNPP. Of the affected patients, 674 had demyelinating CMT, 340 had axonal CMT, and 192 had HNPP; of those, 51%, 13%, and 35% had a genetic diagnosis. Of all patients genetically identified, 89.3% of the 429 patients with demyelinating CMT were detected using PMP22 duplication/deletion analysis (74.8%), GJB1/Cx32 (8.9%), or MPZ/P0 (5.6%) mutation analysis. Of the 57 patients with genetically-identified axonal CMT, 84.2% were identified using GJB1/Cx32 (42.1%), MFN2 (33.3%), or MPZ/P0 (8.8%) analysis. For patients with MFN2 and PNP22 mutations, there was a range of clinical severity.
 
DiVincenzo et al reported the mutation detection rate for 14 hereditary peripheral neuropathy-associated genes in a cohort of 17,880 patients with CMT disease who were referred to a commercial genetic testing laboratory (DiVincenzo, 2014). Test methods included Sanger sequencing assay (n=100,102 assays), next-generation sequencing (NGS) assays (n=2338), and multiplex ligation-dependent probe amplification assays (n=21,990). The genes evaluated include PMP22, GJB1, MPZ, MFN2, SH3TC2, GDAP1, NEFL, LITAF, GARS, HSPB1, FIG4, EGR2, PRX, and RAB7A. Of the patient cohort, 18.5% (n=3312) had a genetic abnormality detected. Among those with a genetic abnormality in a CMT-related gene, 94.9% were positive in one of four genes (PMP22, GJB1, MPZ, or MFN2). Duplications (56.7%) or deletions (21.9%) in the PMP22 gene were the most common finding, followed by GJB1 mutations (6.7%). Several studies have evaluated broader panel tests for hereditary peripheral neuropathies. Hoyer et al reported the yield of testing with next-generation sequencing with a custom panel including 32 CMT genes and 19 other genes associated with inherited neuropathies among 81 families with CMT (Hoyer, 2014). Pathogenic or likely pathogenic gene mutations were identified in 37 (46%) of families. OF the 38 families with CMT1, 55% (21/38) had certain or likely pathogenic genotypes identified (11 copy number variants and 10 point mutations). Of the 33 families with CMT2, 36% (12/33) had certain or likely
pathogenic genotypes identified. In 2015, Drew et al reported results of whole exome sequencing (WES) for 110 patients with inherited peripheral neuropathies who had previously had negative genetic testing for mutations in common genes associated with peripheral neuropathies.35 The authors identified 41 missense sequence variants in genes known to be associated with inherited peripheral neuropathies, 9 of which were considered pathogenic, 12 of which were considered novel variants potentially implicated in the disease, and 20 of which were considered polymorphisms.
 
Few genotype-phenotype correlations for CMT 2 are known. Considerable variability of phenotype has been observed within families with CMT2A In summary, genetic testing for most of the inherited peripheral neuropathies is commercially available. The analytic validity of mutation testing for these diseases is high. For the evaluation of hereditary motor and sensory peripheral neuropathies (Charcot-Marie-Tooth [CMT] types 1, 2, 4, and X-linked CMT) and for hereditary neuropathy with liability to pressure palsies (HNPP), clinical specificity is reported to be high. The clinical sensitivity has been more variable, but tends to be higher for CMT1. However, the clinical utility of genetic testing to confirm a diagnosis in a patient with a clinical diagnosis of an inherited peripheral neuropathy is unknown. No studies were identified that evaluate health outcomes for patients managed with genetic testing. Direct evidence for improved health outcomes with use of genetic testing for hereditary motor and sensory peripheral neuropathies and HNPP is limited. Although a genetic testing to confirm a diagnosis is feasible, the changes in management that would occur based on that information are not well-defined. Therefore, the available evidence is insufficient to determine that genetic testing for mutations associated with the hereditary motor and sensory peripheral neuropathies and HNPP improves the net outcome for patients with these conditions.
 
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2016 cross-sectional study of 520 children and adolescents with CMT found variability in CMT-related symptoms across the 5 most commonly represented subtypes (Cornett, 2016).
 
CMT subtypes are characterized by variants in one of several myelin genes, which lead to abnormalities in myelin structure, function, or upkeep. There are 7 subtypes of CMT, with type 1 and 2 representing the most common hereditary peripheral neuropathies.
 
Currently there is no therapy to slow the progression of neuropathy for the inherited peripheral neuropathies. A 2015 systematic review of exercise therapies for CMT including 9 studies described in 11 articles reported significant improvements with in functional activities and physiological adaptations with exercise (Sman, 2015).
 
In 2016, Rudnik-Schoneborn and colleagues reported results from genetic testing of 1206 index patients and 124 affected relatives who underwent genetic testing at a single reference laboratory from 2001 to 2012 (Rudnik-Schoneborn, 2016). Patients were referred by neurologic or genetic centers throughout Germany, and were grouped by age at onset (early infantile [<2 years], childhood [2-10 years], juvenile [10-20 years], adult [20-50 years], late adult [>50 years]), and by electroneurographic findings. Molecular genetic methods changed over the course of the study, and testing was tiered depending on patient features and family history. Of the 674 index patients with a demyelinating CMT phenotype on nerve conduction studies, 343 (51%) had a genetic diagnosis; of the 340 index patients with an axonal CMT phenotype, 45 (13%) had a genetic diagnosis; and of the 192 with HNPP, 67 (35%) had a genetic diagnosis. The most common genetic diagnoses differed by nerve conduction phenotype: of the 429 patients genetically identified with demyelinating CMT (index and secondary), 89.3% were detected with PMP22 deletion or duplication (74.8%), GJB1/Cx32 (8.9%), or MPZ/P0 (5.6%) variant analysis. In contrast, of the 57 patients genetically identified with axonal CMT (index and secondary), 84.3% were detected with GJB1/Cx32 (42.1%), MFN2 (33.3%), or MPZ/P0 (8.8%) variant analysis.
 
In an earlier study, Gess and colleagues reported on sequential genetic testing for CMT-related genes from 776 patients at a single center for suspected inherited peripheral neuropathies from 2004 to 2012 (Gess, 2013). Most patients (n=624) were treated in the same center. The test strategy varied based on electrophysiologic data and family history. The yield of genetic testing was 66% (233/355) in patients with CMT1, 35% (53/151) in patients with CMT2, and 64% (53/83) in patients with HNPP. Duplications on chromosome 17 were the most common variants in CMT1 (77%), followed by GJB1 (13%) and MPZ (8%) variants among those with positive genetic tests. For CMT2 patients, GJB2 (30%) and MFN2 (23%) variants were most common among those with positive genetic tests.
 
Ostern and colleagues reported on a retrospective analysis of cases of CMT diagnostic testing referred to a single reference laboratory in Norway from 2004 to 2010 (Ostern, 213). Genetic testing was stratified based on clinical information supplied on patient requisition forms based on age of onset of symptoms, prior testing, results from motor NCV, and patterns of inheritance. The study sample included 435 index cases, of a total of 549 CMT cases tested (other tests were for at risk family members or other reasons.) Patients were grouped based on whether they had symptoms of polyneuropathy, classical CMT, with or without additional symptoms or changes on imaging, or had atypical features or the physician suspected an alternative diagnosis. Among the cases tested, 72 (16.6%) were found to be variant-positive, all of whom had symptoms of CMT. Most (69/72 [95.8%]) of the positive molecular genetic findings were PMP22 region duplications or sequence variants in MPZ, GJB1, or MFN2 genes.
 
Murphy and colleagues reported on the yield of sequential testing for CMT-related gene variants from 1607 patients with testing sent to a single center (Murphy, 2012). Of the 916 patients seen in the authors’ clinic, 601 (65.6%) had a primary inherited neuropathy, including 425 with CMT and46 with HNPP. Of the 425 with a clinical diagnosis of CMT, 240 had CMT1 (56.5%), and 115 (27.1%) had CMT2. Of those with CMT, 266 (62.6%) of 425 received a genetic diagnosis, most frequently (92%) with a variant in 1 of 4 genes (PMP22 duplication, and GJB1, MPZ, and MFN2).
 
Sanmaneechai and colleagues genotype-phenotype correlations in patients with CMT1B in terms of variants in the MPZ gene in a cohort of 103 patients from 71 families (Sanmaneechai, 2015). Patients underwent standardized clinical assessments and clinical electrophysiology. There were 47 different MPZ variants and 3 characteristic ages of onset, infantile (age range, 0-5 years), childhood (age range, 6-20 years), and adult (age range, ≥21 years). Specific variants clustered by age group, with only 2 variants found in more than 1 age group.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed below:
 
(NCT01193075) Natural History Evaluation of Charcot Marie tooth Disease (CMT) Type (CMTB1), 2A (CMT2A), 4A (CMT4A), 4C (CMT4C), and Others; planned enrollment 5000; projected completion date December 2016.
 
(NCT01193088) Genetics of Charcot Marie Tooth Disease (CMT) – Modifiers of CMT1A, New Causes of CMT; planned enrollment 1050; projected completion date December 2016.
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Uchôa Cavalcanti reported on results from genetic testing of 503 patients (94 families and 192 unrelated individuals) who underwent testing in a Brazilian neuromuscular outpatient clinic from 2015 to 2020 (Uchoa, 2021). The diagnosis of CMT was established based on the presence of slowly progressive, motor and sensory neuropathy, independent of any family history. Patients were assessed utilizing clinical and neurophysiological data along with targeted gene panel sequencing. Among the 503 patients, a genetic diagnosis was reported in 394 patients (77 families and 120 unrelated individuals). The following confirmed genetic diagnoses were identified: demyelinating CMT (n=317), intermediate CMT (n=34), and axonal CMT (n=43). The genetic diagnosis rate in probands was 68.9% (197/286). The most common causative genes were PMP22 duplication GJB1, MFN2, GDAP1, MPZ, PMP22 point mutation, NEFL, SBF2, and SH3TC2.
 
A study was conducted on 2,517 participants with a suspected diagnosis of Charcot Mare Tooth (Volodarsky, 2021). Participants were referred to a molecular genetic laboratory where a 34 gene next-generation sequencing panel was conducted. The study resulted in a diagnostic yield of 440 of the participants (17.5%). Six genes constituted 80% of the overall results.
 
In 2020, the American Academy of Family Physicians recommended genetic testing for a patient with suspected peripheral neuropathy, if basic blood tests are negative, electrodiagnostic studies suggest an axonal etiology and diseases such as diabetes, toxic medications, thyroid disease, vitamin deficiency, and vasculitis can be ruled out (Castelli, 2020).
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.
 
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2025. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Record et al reported the use of whole genome sequencing to diagnose CMT (Record, 2024). Among the 1515 patients with a clinical diagnosis of CMT or a related disorder who were referred to a single inherited neuropathy center, the genetic diagnostic yield was 76.9%. The most common diagnosis was CMT1 (41.0%), followed by CMT2 (19.4%), intermediate CMT (13.5%); 4.8% of patients had HNPP. The most common genetic diagnoses were PMP22 duplication, GJB1, PMP22 deletion, and MFN2.
CPT/HCPCS:
81324PMP22 (peripheral myelin protein 22) (eg, Charcot Marie Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis
81325PMP22 (peripheral myelin protein 22) (eg, Charcot Marie Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis
81326PMP22 (peripheral myelin protein 22) (eg, Charcot Marie Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; known familial variant
81403Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of &gt;10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence ARX (aristaless-related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), duplication/deletion analysis CEL (carboxyl ester lipase [bile salt-stimulated lipase]) (eg, maturity-onset diabetes of the young [MODY]), targeted sequence analysis of exon 11 (eg, c.1785delC, c.1686delT) CTNNB1 (catenin [cadherin-associated protein], beta 1, 88kDa) (eg, desmoid tumors), targeted sequence analysis (eg, exon 3) DAZ/SRY (deleted in azoospermia and sex determining region Y) (eg, male infertility), common deletions (eg, AZFa, AZFb, AZFc, AZFd) DNMT3A (DNA [cytosine-5-]-methyltransferase 3 alpha) (eg, acute myeloid leukemia), targeted sequence analysis (eg, exon 23) EPCAM (epithelial cell adhesion molecule) (eg, Lynch syndrome), duplication/deletion analysis F8 (coagulation factor VIII) (eg, hemophilia A), inversion analysis, intron 1 and intron 22A F12 (coagulation factor XII [Hageman factor]) (eg, angioedema, hereditary, type III; factor XII deficiency), targeted sequence analysis of exon 9 FGFR3 (fibroblast growth factor receptor 3) (eg, isolated craniosynostosis), targeted sequence analysis (eg, exon 7) (For targeted sequence analysis of multiple FGFR3 exons, use 81404) GJB1 (gap junction protein, beta 1) (eg, Charcot-Marie-Tooth X-linked), full gene sequence GNAQ (guanine nucleotide-binding protein G[q] subunit alpha) (eg, uveal melanoma), common variants (eg, R183, Q209) Human erythrocyte antigen gene analyses (eg, SLC14A1 [Kidd blood group], BCAM [Lutheran blood group], ICAM4 [Landsteiner-Wiener blood group], SLC4A1 [Diego blood group], AQP1 [Colton blood group], ERMAP [Scianna blood group], RHCE [Rh blood group, CcEe antigens], KEL [Kell blood group], DARC [Duffy blood group], GYPA, GYPB, GYPE [MNS blood group], ART4 [Dombrock blood group]) (eg, sickle-cell disease, thalassemia, hemolytic transfusion reactions, hemolytic disease of the fetus or newborn), common variants HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), exon 2 sequence KCNC3 (potassium voltage-gated channel, Shaw-related subfamily, member 3) (eg, spinocerebellar ataxia), targeted sequence analysis (eg, exon 2) KCNJ2 (potassium inwardly-rectifying channel, subfamily J, member 2) (eg, Andersen-Tawil syndrome), full gene sequence KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) (eg, familial hyperinsulinism), full gene sequence Killer cell immunoglobulin-like receptor (KIR) gene family (eg, hematopoietic stem cell transplantation), genotyping of KIR family genes Known familial variant not otherwise specified, for gene listed in Tier 1 or Tier 2, or identified during a genomic sequencing procedure, DNA sequence analysis, each variant exon (For a known familial variant that is considered a common variant, use specific common variant Tier 1 or Tier 2 code) MC4R (melanocortin 4 receptor) (eg, obesity), full gene sequence MICA (MHC class I polypeptide-related sequence A) (eg, solid organ transplantation), common variants (eg, *001, *002) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), full gene sequence MT-TS1 (mitochondrially encoded tRNA serine 1) (eg, nonsyndromic hearing loss), full gene sequence NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), duplication/deletion analysis NHLRC1 (NHL repeat containing 1) (eg, progressive myoclonus epilepsy), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), duplication/deletion analysis PLN (phospholamban) (eg, dilated cardiomyopathy, hypertrophic cardiomyopathy), full gene sequence RHD (Rh blood group, D antigen) (eg, hemolytic disease of the fetus and newborn, Rh maternal/fetal compatibility), deletion analysis (eg, exons 4, 5, and 7, pseudogene) RHD (Rh blood group, D antigen) (eg, hemolytic disease of the fetus and newborn, Rh maternal/fetal compatibility), deletion analysis (eg, exons 4, 5, and 7, pseudogene), performed on cell-free fetal DNA in maternal blood (For human erythrocyte gene analysis of RHD, use a separate unit of 81403) SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), duplication/deletion analysis TWIST1 (twist homolog 1 [Drosophila]) (eg, Saethre-Chotzen syndrome), duplication/deletion analysis UBA1 (ubiquitin-like modifier activating enzyme 1) (eg, spinal muscular atrophy, X-linked), targeted sequence analysis (eg, exon 15) VHL (von Hippel-Lindau tumor suppressor) (eg, von Hippel-Lindau familial cancer syndrome), deletion/duplication analysis VWF (von Willebrand factor) (eg, von Willebrand disease types 2A, 2B, 2M), targeted sequence analysis (eg, exon 28)
81404Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) ACADS (acyl-CoA dehydrogenase, C-2 to C-3 short chain) (eg, short chain acyl-CoA dehydrogenase deficiency), targeted sequence analysis (eg, exons 5 and 6) AQP2 (aquaporin 2 [collecting duct]) (eg, nephrogenic diabetes insipidus), full gene sequence ARX (aristaless related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), full gene sequence AVPR2 (arginine vasopressin receptor 2) (eg, nephrogenic diabetes insipidus), full gene sequence BBS10 (Bardet-Biedl syndrome 10) (eg, Bardet-Biedl syndrome), full gene sequence BTD (biotinidase) (eg, biotinidase deficiency), full gene sequence C10orf2 (chromosome 10 open reading frame 2) (eg, mitochondrial DNA depletion syndrome), full gene sequence CAV3 (caveolin 3) (eg, CAV3-related distal myopathy, limb-girdle muscular dystrophy type 1C), full gene sequence CD40LG (CD40 ligand) (eg, X-linked hyper IgM syndrome), full gene sequence CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence CLRN1 (clarin 1) (eg, Usher syndrome, type 3), full gene sequence COX6B1 (cytochrome c oxidase subunit VIb polypeptide 1) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence CPT2 (carnitine palmitoyltransferase 2) (eg, carnitine palmitoyltransferase II deficiency), full gene sequence CRX (cone-rod homeobox) (eg, cone-rod dystrophy 2, Leber congenital amaurosis), full gene sequence CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (eg, primary congenital glaucoma), full gene sequence EGR2 (early growth response 2) (eg, Charcot-Marie-Tooth), full gene sequence EMD (emerin) (eg, Emery-Dreifuss muscular dystrophy), duplication/deletion analysis EPM2A (epilepsy, progressive myoclonus type 2A, Lafora disease [laforin]) (eg, progressive myoclonus epilepsy), full gene sequence FGF23 (fibroblast growth factor 23) (eg, hypophosphatemic rickets), full gene sequence FGFR2 (fibroblast growth factor receptor 2) (eg, craniosynostosis, Apert syndrome, Crouzon syndrome), targeted sequence analysis (eg, exons 8, 10) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), targeted sequence analysis (eg, exons 8, 11, 12, 13) FHL1 (four and a half LIM domains 1) (eg, Emery-Dreifuss muscular dystrophy), full gene sequence FKRP (fukutin related protein) (eg, congenital muscular dystrophy type 1C [MDC1C], limb-girdle muscular dystrophy [LGMD] type 2I), full gene sequence FOXG1 (forkhead box G1) (eg, Rett syndrome), full gene sequence FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), evaluation to detect abnormal (eg, deleted) alleles FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), characterization of haplotype(s) (ie, chromosome 4A and 4B haplotypes) GH1 (growth hormone 1) (eg, growth hormone deficiency), full gene sequence GP1BB (glycoprotein Ib [platelet], beta polypeptide) (eg, Bernard-Soulier syndrome type B), full gene sequence (For common deletion variants of alpha globin 1 and alpha globin 2 genes, use 81257) HNF1B (HNF1 homeobox B) (eg, maturity-onset diabetes of the young [MODY]), duplication/deletion analysis HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), full gene sequence HSD3B2 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) (eg, 3-beta-hydroxysteroid dehydrogenase type II deficiency), full gene sequence HSD11B2 (hydroxysteroid [11-beta] dehydrogenase 2) (eg, mineralocorticoid excess syndrome), full gene sequence HSPB1 (heat shock 27kDa protein 1) (eg, Charcot-Marie-Tooth disease), full gene sequence INS (insulin) (eg, diabetes mellitus), full gene sequence KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) (eg, Bartter syndrome), full gene sequence KCNJ10 (potassium inwardly-rectifying channel, subfamily J, member 10) (eg, SeSAME syndrome, EAST syndrome, sensorineural hearing loss), full gene sequence LITAF (lipopolysaccharide-induced TNF factor) (eg, Charcot-Marie-Tooth), full gene sequence MEFV (Mediterranean fever) (eg, familial Mediterranean fever), full gene sequence MEN1 (multiple endocrine neoplasia I) (eg, multiple endocrine neoplasia type 1, Wermer syndrome), duplication/deletion analysis MMACHC (methylmalonic aciduria [cobalamin deficiency] cblC type, with homocystinuria) (eg, methylmalonic acidemia and homocystinuria), full gene sequence MPV17 (MpV17 mitochondrial inner membrane protein) (eg, mitochondrial DNA depletion syndrome), duplication/deletion analysis NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), full gene sequence NDUFA1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 1, 7.5kDa) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFAF2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFS4 (NADH dehydrogenase [ubiquinone] Fe-S protein 4, 18kDa [NADH-coenzyme Q reductase]) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) (eg, spastic paraplegia), full gene sequence NLGN4X (neuroligin 4, X-linked) (eg, autism spectrum disorders), duplication/deletion analysis NPC2 (Niemann-Pick disease, type C2 [epididymal secretory protein E1]) (eg, Niemann-Pick disease type C2), full gene sequence NR0B1 (nuclear receptor subfamily 0, group B, member 1) (eg, congenital adrenal hypoplasia), full gene sequence PDX1 (pancreatic and duodenal homeobox 1) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), full gene sequence PLP1 (proteolipid protein 1) (eg, Pelizaeus-Merzbacher disease, spastic paraplegia), duplication/deletion analysis PQBP1 (polyglutamine binding protein 1) (eg, Renpenning syndrome), duplication/deletion analysis PRNP (prion protein) (eg, genetic prion disease), full gene sequence PROP1 (PROP paired-like homeobox 1) (eg, combined pituitary hormone deficiency), full gene sequence PRPH2 (peripherin 2 [retinal degeneration, slow]) (eg, retinitis pigmentosa), full gene sequence PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) (eg, LEOPARD syndrome), targeted sequence analysis (eg, exons 7, 12, 14, 17) RET (ret proto-oncogene) (eg, multiple endocrine neoplasia, type 2B and familial medullary thyroid carcinoma), common variants (eg, M918T, 2647_2648delinsTT, A883F) RHO (rhodopsin) (eg, retinitis pigmentosa), full gene sequence RP1 (retinitis pigmentosa 1) (eg, retinitis pigmentosa), full gene sequence SCN1B (sodium channel, voltage-gated, type I, beta) (eg, Brugada syndrome), full gene sequence SCO2 (SCO cytochrome oxidase deficient homolog 2 [SCO1L]) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary paraganglioma-pheochromocytoma syndrome), duplication/deletion analysis SDHD (succinate dehydrogenase complex, subunit D, integral membrane protein) (eg, hereditary paraganglioma), full gene sequence SGCG (sarcoglycan, gamma [35kDa dystrophin-associated glycoprotein]) (eg, limb-girdle muscular dystrophy), duplication/deletion analysis SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), full gene sequence SLC16A2 (solute carrier family 16, member 2 [thyroid hormone transporter]) (eg, specific thyroid hormone
81405Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities (When performing cytogenomic [genome-wide] analysis, for constitutional chromosomal abnormalities. See 81228, 81229, 81349)
81406Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons) ACADVL (acyl-CoA dehydrogenase, very long chain) (eg, very long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence ACTN4 (actinin, alpha 4) (eg, focal segmental glomerulosclerosis), full gene sequence AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence AIRE (autoimmune regulator) (eg, autoimmune polyendocrinopathy syndrome type 1), full gene sequence ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (eg, pyridoxine-dependent epilepsy), full gene sequence ANO5 (anoctamin 5) (eg, limb-girdle muscular dystrophy), full gene sequence ANOS1 (anosmin-1) (eg, Kallmann syndrome 1), full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence ASS1 (argininosuccinate synthase 1) (eg, citrullinemia type I), full gene sequence ATL1 (atlastin GTPase 1) (eg, spastic paraplegia), full gene sequence ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) (eg, familial hemiplegic migraine), full gene sequence ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence BBS1 (Bardet-Biedl syndrome 1) (eg, Bardet-Biedl syndrome), full gene sequence BBS2 (Bardet-Biedl syndrome 2) (eg, Bardet-Biedl syndrome), full gene sequence BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence BEST1 (bestrophin 1) (eg, vitelliform macular dystrophy), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), full gene sequence BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 [seipin]) (eg, Berardinelli-Seip congenital lipodystrophy), full gene sequence BTK (Bruton agammaglobulinemia tyrosine kinase) (eg, X-linked agammaglobulinemia), full gene sequence CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) (eg, Brugada syndrome), full gene sequence CAPN3 (calpain 3) (eg, limb-girdle muscular dystrophy [LGMD] type 2A, calpainopathy), full gene sequence CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), full gene sequence CDH1 (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer), full gene sequence CDKL5 (cyclin-dependent kinase-like 5) (eg, early infantile epileptic encephalopathy), full gene sequence CLCN1 (chloride channel 1, skeletal muscle) (eg, myotonia congenita), full gene sequence CLCNKB (chloride channel, voltage-sensitive Kb) (eg, Bartter syndrome 3 and 4b), full gene sequence CNTNAP2 (contactin-associated protein-like 2) (eg, Pitt-Hopkins-like syndrome 1), full gene sequence COL6A2 (collagen, type VI, alpha 2) (eg, collagen type VI-related disorders), duplication/deletion analysis CPT1A (carnitine palmitoyltransferase 1A [liver]) (eg, carnitine palmitoyltransferase 1A [CPT1A] deficiency), full gene sequence CRB1 (crumbs homolog 1 [Drosophila]) (eg, Leber congenital amaurosis), full gene sequence CREBBP (CREB binding protein) (eg, Rubinstein-Taybi syndrome), duplication/deletion analysis DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence DLAT (dihydrolipoamide S-acetyltransferase) (eg, pyruvate dehydrogenase E2 deficiency), full gene sequence DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence DSC2 (desmocollin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence DSG2 (desmoglein 2) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 10), full gene sequence DSP (desmoplakin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 8), full gene sequence EFHC1 (EF-hand domain [C-terminal] containing 1) (eg, juvenile myoclonic epilepsy), full gene sequence EIF2B3 (eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B4 (eukaryotic translation initiation factor 2B, subunit 4 delta, 67kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence ENG (endoglin) (eg, hereditary hemorrhagic telangiectasia, type 1), full gene sequence EYA1 (eyes absent homolog 1 [Drosophila]) (eg, branchio-oto-renal [BOR] spectrum disorders), full gene sequence F8 (coagulation factor VIII) (eg, hemophilia A), duplication/deletion analysis FAH (fumarylacetoacetate hydrolase [fumarylacetoacetase]) (eg, tyrosinemia, type 1), full gene sequence FASTKD2 (FAST kinase domains 2) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae]) (eg, Charcot-Marie-Tooth disease), full gene sequence FTSJ1 (FtsJ RNA methyltransferase homolog 1 [E. coli]) (eg, X-linked mental retardation 9), full gene sequence FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence GALC (galactosylceramidase) (eg, Krabbe disease), full gene sequence GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence GARS (glycyl-tRNA synthetase) (eg, Charcot-Marie-Tooth disease), full gene sequence GCDH (glutaryl-CoA dehydrogenase) (eg, glutaricacidemia type 1), full gene sequence GCK (glucokinase [hexokinase 4]) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence GLUD1 (glutamate dehydrogenase 1) (eg, familial hyperinsulinism), full gene sequence GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) (eg, inclusion body myopathy 2 [IBM2], Nonaka myopathy), full gene sequence GRN (granulin) (eg, frontotemporal dementia), full gene sequence HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein] alpha subunit) (eg, long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein], beta subunit) (eg, trifunctional protein deficiency), full gene sequence HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence HLCS (HLCS holocarboxylase synthetase) (eg, holocarboxylase synthetase deficiency), full gene sequence HMBS (hydroxymethylbilane synthase) (eg, acute intermittent porphyria), full gene sequence HNF4A (hepatocyte nuclear factor 4, alpha) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence IDUA (iduronidase, alpha-L-) (eg, mucopolysaccharidosis type I), full gene sequence INF2 (inverted formin, FH2 and WH2 domain containing) (eg, focal segmental glomerulosclerosis), full gene sequence IVD (isovaleryl-CoA dehydrogenase) (eg, isovaleric acidemia), full gene sequence JAG1 (jagged 1) (eg, Alagille syndrome), duplication/deletion analysis JUP (junction plakoglobin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence KCNH2 (potassium voltage-gated channel, subfamily H [eag-related], member 2) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ2 (potassium voltage-gated channel, KQT-like subfamily, member 2) (eg, epileptic encephalopathy), full gene sequence LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy, myofibrillar myopathy), full gene sequence LDLR (low den
81448Hereditary peripheral neuropathies (eg, Charcot Marie Tooth, spastic paraplegia), genomic sequence analysis panel, must include sequencing of at least 5 peripheral neuropathy related genes (eg, BSCL2, GJB1, MFN2, MPZ, REEP1, SPAST, SPG11, SPTLC1)
81479Unlisted molecular pathology procedure
References: Bird TD.(2015) Charcot-Marie-Tooth Hereditary Neuropathy Overview. In: Pagon RA, Bird TD, Dolan CR, et al., eds. GeneReviews. Seattle (WA)2015 (last revision).

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