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Genetic Testing for Diagnosis of Inherited Peripheral Neuropathies AHS – M2072
Commercial Medical Policy
Origination: 01/2019
Last Review: 07/2025

Description of Procedure or Service

The inherited peripheral neuropathies are a heterogeneous group of diseases that may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner. The inherited peripheral neuropathies can be divided into hereditary motor and sensory neuropathies (such as Charcot-Marie-Tooth disease), hereditary neuropathy with liability to pressure palsies, hereditary sensory and autonomic neuropathies, and other miscellaneous types (e.g., hereditary brachial plexopathy, giant axonal neuropathy). In addition to clinical presentation, nerve conduction studies, and family history, genetic testing can be used to diagnose specific inherited peripheral neuropathies.

When pursuing genetic testing for inherited peripheral neuropathies, genetic counseling is strongly recommended.

Related Policies:

Nerve Fiber Density Testing AHS – M2112

General Genetic Testing, Germline Disorders AHS – M2145

General Genetic Testing, Somatic Disorders AHS – M2146

Prenatal Screening (Genetic) AHS – M2179

Celiac Disease Testing AHS – G2043

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for genetic testing for diagnosis of inherited peripheral neuropathies when it is determined the medical criteria or reimbursement guidelines below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore, member benefit language should be reviewed before applying the terms of this medical policy.

When Genetic Testing for Diagnosis of Inherited Peripheral Neuropathies is covered

  1. For individuals with clinical features of Charcot-Marie-Tooth (CMT) disease, but for whom a definitive diagnosis cannot be made without genetic testing, genetic testing for PMP22 deletions/duplication, GJB1pathogenic or likely pathogenic (P/LP) variants, and/or MFN2 P/LP variants is considered medically necessary.
  2. For individuals with clinical features of CMT disease who have tested negative for common deleterious variants (PMP22 deletions/duplication; GJB1 or MFN 2P/LP variants), single gene or multi-gene panel testing for CMT disease risk genes is considered medically necessary.
  3. For asymptomatic individuals who have a close blood relative (see Note 1) with a known deleterious P/LP variant in a CMT gene, genetic testing for the known familial mutation is considered medically necessary.
  4. For individuals who are clinically suspected of having hereditary neuropathy with liability to pressure palsies (HNPP), but for whom a definitive diagnosis cannot be made without genetic testing, genetic testing for PMP22 deletions and duplications is considered medically necessary.
  5. For individuals who are clinically suspected of having hereditary motor neuropathy (HMN), but for whom a definitive diagnosis cannot be made without genetic testing, genetic testing for BSCL2 P/LP variants is considered medically necessary.

Note 1: Close blood relatives include first-degree relatives (e.g., parents, siblings, and children), second-degree relatives (e.g., grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings), and third-degree relatives (great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins).

Note 2: For two or more gene tests being run on the same platform please refer to AHS-R2162 Laboratory Procedures Medical Policy.

When Genetic Testing for Diagnosis of Inherited Peripheral Neuropathies is not covered

Genetic Testing for Diagnosis of Inherited Peripheral Neuropathies is not covered when the above criteria are not met.

Policy Guidelines

Background

Peripheral neuropathies encompass the set of disorders that primarily lead to peripheral nerve dysfunction. Symptoms typically include weakness of muscles at extremities, spine curvature, and loss of sensation at extremities. Neuropathies may be caused by a variety of different factors, such as metabolic issues (including Fabry disease, Niemann-Pick disease, etc.) or present as a secondary symptom to another condition (such as Tangier disease).

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor sensory neuropathy, is a group of progressive disorders that affect the peripheral nerves. CMT is caused by a mutation in one of several myelin genes that result in defects in myelin structure, maintenance, or function within peripheral nerves. CMT disease is one of the most common inherited neurological disorders, affecting approximately one in 2,500 people in the United States.

Symptoms

The neuropathy of CMT affects both motor and sensory nerves. Symptoms usually start in childhood and have a gradual progression. The severity of symptoms varies greatly among individuals and even among family members with the disease and gene mutation. Typical symptoms include the following:

  • “Weakness or paralysis in the foot and lower leg muscles, making it hard to lift the foot (foot drop)
  • A high-stepping walking pattern with frequent tripping or falling
  • Balance problems
  • Foot deformities, like high arches and curled toes (hammertoes)
  • Lower legs with an "inverted champagne bottle" shape due to the loss of muscle bulk
  • Trouble feeling heat, cold, and touch
  • Possible hand weakness and atrophy, causing difficulty with small, precise movements
  • Decreased ability to sense vibrations or know body position (proprioception)
  • Curved spine (scoliosis)
  • A hip joint out of its normal position (hip displacement)
  • A chronic shortening of muscles or tendons around joints (contractures)
  • Muscle cramps
  • Nerve pain.”

Pain can range from mild to severe, and some people may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people living with CMT experience tremor, and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected.

Causes

Charcot-Marie-Tooth is caused by mutations in genes that produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. Although different proteins are abnormal in different forms of CMT disease, all mutations affect the normal function of the peripheral nerves. There is little correlation between the genotype and phenotype of CMT; it is common to see differing mutations result in various clinical phenotypes all within the same gene.

Pattern of Inheritance

The pattern of inheritance varies with the type of CMT disease. Charcot-Marie-Tooth disease type 1 (CMT1), most cases of Charcot-Marie-Tooth disease type 2 (CMT2), and most intermediate forms are inherited in an autosomal dominant pattern. Charcot-Marie-Tooth disease type 4 (CMT4), a few CMT2 subtypes, and some intermediate forms are inherited in an autosomal recessive pattern. Charcot-Marie-Tooth disease type X (CMTX) is inherited in an X-linked pattern. Some cases of CMT disease result from a new mutation and occur in people with no history of the disorder in their family. In rare cases the gene mutation causing CMT disease is a new mutation which occurs spontaneously in the individual's genetic material and has not been passed down through the family.

CMT1

Charcot-Marie-Tooth disease type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and are usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. The six subtypes of CMT1 shown in Table 1 are clinically indistinguishable and are designated solely on molecular findings.

Table 1: Molecular Genetics of CMT1

Locus Name

Proportion of CMT1 (excluding CMTX)

Gene

Protein Product

CMT1A

70%-80%

PMP22

Peripheral myelin protein 22

CMT1B

10%-12%

MPZ

Myelin protein P0

CMT1C

~1%

LITAF

Lipopolysaccharide induced tumor necrosis factor-alpha factor

CMT1D

Unknown

EGR2

Early growth response protein 2

CMT1E

~1%

PMP22

Peripheral myelin protein 22
(sequence changes)

CMT1F/2E

Unknown

NEFL

Neurofilament light polypeptide

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant disease that results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP-22). Overexpression of this gene causes the structure and function of the myelin sheath to be abnormal. A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP-22 genes. In this case, abnormally low levels of the PMP-22 gene result in episodic, recurrent demyelinating neuropathy.

Charcot-Marie-Tooth disease type 1B (CMT1B) is an autosomal dominant disease caused by mutations in the gene that carries the instructions for manufacturing the MPZ, which is another critical component of the myelin sheath. Most of these mutations are point mutations. As a result of abnormalities in MPZ, CMT1B produces symptoms similar to those found in CMT1A.

Other less common causes genetic causes of CMT1 result from mutations within LITAF, EGR2, PMP22, and NEFL genes, respectively.

CMT2

Charcot-Marie-Tooth disease type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy. Axonal peripheral neuropathy shows extensive clinical overlap with CMT1. In general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1. It is less common than CMT1. CMT2A, the most common axonal form of CMT, is caused by mutations in Mitofusin 2, a protein associated with mitochondrial fusion. Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1. Additionally, symptoms for CMT2 may have vocal cord or phrenic nerve involvement, causing speech or respiratory problems. 

Table 2: Molecular Genetics of CMT2 

Locus

Proportion of CMT

Gene / Chromosome Locus

Protein Product

CMT2A1

Unknown

KIF1B

Kinesin-like protein KIF1B

CMT2A21

20%

MFN2

Mitofusin-2

CMT2B

Unknown

RAB7A

Ras-related protein Rab-7

CMT2B1

Unknown

LMNA

Lamin A/C

CMT2B2

Unknown

MED25

Mediator of RNA polymerase II transcription subunit 25

CMT2C2

Unknown

TRPV4

Transient receptor potential cation channel subfamily V member 4

CMT2D3

3%

GARS

Glycyl-tRNA synthetase

CMT2E/1F4

4%

NEFL

Neurofilament light polypeptide

CMT2F

Unknown

HSPB1

Heat-shock protein beta-1

CMT2G

Unknown

12q12-q13

Unknown

CMT2H/2K

5%

GDAP1

Ganglioside-induced differentiation-associated protein-1

CMT2I/2J

Unknown

MPZ

Myelin protein P0

CMT2L

Unknown

HSPB8

Heat-shock protein beta-8

CMT2N

Unknown

AARS

Alanine--tRNA ligase, cytoplasmic

CMT2O

Unknown

DYNC1H1

Cytoplasmic dynein 1 heavy chain 1

CMT2P

Unknown

LRSAM1

E3 ubiquitin-protein ligase LRSAM1

CMT2S

Unknown

IGHMBP2

DNA-binding protein SMUBP-2

CMT2T

Unknown

DNAJB2

DnaJ homolog subfamily B member 2

CMT2U

Unknown

MARS

Methionine--tRNA ligase, cytoplasmic

CMT3

Dejerine-Sottas disease (CMT3), is a severe demyelinating neuropathy that begins in infancy. Infants have severe muscle atrophy, weakness, and sensory problems. This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively.

CMT4

Charcot-Marie-Tooth disease type 4 (CMT4) comprises several different subtypes of autosomal recessive demyelinating motor and sensory axonal neuropathies. Each neuropathy subtype is caused by a different genetic mutation, may affect a particular ethnic population, and produces distinct physiologic or clinical characteristics. Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. Several genes have been identified as causing CMT4, including GDAP1 (CMT4A), MTMR13 (CMT4B1), MTMR2 (CMT4B2), SH3TC2 (CMT4C), NDG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FDG4 (CMT4H), and FIG4 (CMT4J).

Table 3: Molecular Genetics of CMT4

Locus Name

Proportion of CMT4

Gene

Protein Product

CMT4A1

Unknown

GDAP1

Ganglioside-induced differentiation-associated protein 1

CMT4B1

MTMR2

Myotubularin-related protein 2

CMT4B2

SBF2

Myotubularin-related protein 13

CMT4C2

SH3TC2

SH3 domain and tetratricopeptide repeats-containing protein 2

CMT4D

NDRG1

Protein NDRG1

CMT4E

EGR2

Early growth response protein 2

CMT4F

PRX

Periaxin

CMT4H3

FGD4

FYVE, RhoGEF and PH domain-containing protein 4

CMT4J4

FIG4

Phosphatidylinositol 3, 5 biphosphate

CMTX

Charcot-Marie-Tooth disease type X (CMTX)  is caused by a point mutation in the connexin-32 gene on the X chromosome. The connexin-32 protein is expressed in Schwann cells, which wrap around nerve axons and make up a single segment of the myelin sheath. CMTX type 1 is characterized by a moderate to severe motor and sensory neuropathy. Hearing loss and central nervous system symptoms may also occur in certain affected families. 

Table 4: Molecular Genetics of CMTX

Disease NameProportion of X-Linked CMT Gene / Chromosome LocusProtein Product
CMTX1190%GJB1Gap junction beta-1 protein (connexin 32)
CMTX22UnknownXp22.2 
CMTX31 Not applicable
CMTX41AIFM1Apoptosis-inducing factor 1
CMTX52PRPS1Ribose-phosphate pyrophosphokinase 1 
CMTX61PDK3Pyruvate dehydrogenase kinase isoform 3

Hereditary Brachial Plexopathy (Hereditary Neuralgic Amyotrophy)

This condition is primarily characterized by painful injuries to the brachial plexus nerves as well as episodic weakness of the shoulder and arm. Other symptoms such as winging of the scapula, short stature, neck folds, small face, and hypotelorism may be present. Nerve conduction velocity is typically normal, and the histopathology of this condition is non-specific. The septin 9 gene (SEPT9) on chromosome 17 has been associated with this condition.

Giant Axonal Neuropathy

This condition is characterized by disorganization of cytoskeletal intermediate filaments stemming from a mutated form of gigaxonin. Patients with this disorder often have a signature physical appearance; red and kinked hair, high foreheads, long eyelashes, and pale complexions are all hallmarks of this condition. The central nervous system may be affected as well with cerebellar dysfunction, spasticity, and potentially intellectual disability as possible symptoms. Nerve biopsy may show axonal loss or another axonal dysfunction. This diagnosis is confirmed by testing of the GAN gene.

Hereditary Sensory and Autonomic Neuropathies (HSANs)

This subsection of disorders primarily encompasses non-motor neuropathies and are characterized by major loss of myelinated and unmyelinated fibers. These conditions are not as common as hereditary motor neuropathies and primarily present with sensory dysfunction, although motor functions may be affected. There are multiple main types of HSAN, each caused by different genes. Genes are associated as shown below:

Disorder

Gene

Clinical features

HSAN1

SPTLC1

Most are autosomal dominant

SPTLC2

Onset often in early adulthood but variable

ATL1

Distal sensory loss, foot ulcers

DNMT1

Preservation of facial sensation

ATL3

Variable muscle wasting and weakness

 

Variable neural deafness and dementia

HSAN2

WNK1/HSN2

Autosomal recessive

FAM134B

Loss of pain, temperature, and tactile sensation

KIF1A

Recurrent infection and fractures of the digits

SCN9A

 

HSAN3 (familial dysautonomia)IKBKAP

Autosomal recessive

Progressive sensorimotor neuropathy

Sympathetic autonomic dysfunction

Smooth tongue without fungiform papillae

HSAN4 (congenital insensitivity to pain with anhidrosis)NTRK1

Autosomal recessive

Profound loss of pain sensitivity

Defects in thermoregulation

Anhydrosis

Mild to moderate mental retardation

Microcephaly

Fungiform papillae are present

HSAN5NGFB

Autosomal recessive

Loss of pain and temperature sensation

Normal muscle strength

Normal reflexes

Normal nerve conduction

HSAN6DST

Autosomal recessive; Ashkenazi Jewish

Autonomic dysfunction

Absent fungiform papillae

Death by age 2 years

HSAN7SCN11A

Autosomal dominant

Congenital insensitivity to pain

Self-mutilation, slow wound healing, painless bone fractures

Gastrointestinal dysfunction

Hyperhidrosis

HSAN8PRDM12

Autosomal recessive

Self-mutilation, insensitivity to pain

Soft tissue injuries

Corneal scarring

Hypohidrosis

HSAN and dementiaPRNP

Autosomal dominant

Dementia

Autonomic dysfunction

Sensory loss

Hereditary sensory neuropathy with spastic paraplegiaCCT5

Autosomal recessive

Spastic paraplegia

Ulcerations of hands and feet

Insensitivity to pain

SCN9A

Autosomal recessive:

Paroxysmal extreme pain disorder

Insensitivity to pain

Primary erythermalgia

Autosomal dominant:

Small fiber neuropathy

 

 

Paroxysmal extreme pain disorder

Primary erythermalgia

Small fiber neuropathy

AD: autosomal dominant; AR: autosomal recessive; HSAN: hereditary sensory and autonomic neuropathy

Other unclassified HSANs exist, such as spastic paraplegia with ulcerations of the hands and feet (associated with CCT5) and sensory neuropathy with ichthyosis and anterior chamber syndrome.

Genetic Testing

Charcot-Marie-Tooth disease is usually diagnosed by an extensive history and physical examination. The clinical diagnosis is then confirmed by electrodiagnostic tests like electromyography and nerve conduction velocity tests, and sometimes by nerve biopsy. Genetic testing is available for most types of CMT, and results are usually enough to confirm a diagnosis. Genetic testing can simplify the diagnosis of CMT by avoiding invasive procedures, such as nerve biopsy. In addition, early diagnosis can facilitate early interventions, including physical therapy. However, most therapies are only supportive (occupational, physical) and generally do not rely on the results of specific genetic testing. A positive genetic test can confirm diagnosis in most people with CMT. But a negative result does not exclude the disease, as an unidentified gene may be missed by DNA sampling.

Genetic testing for CMT is complicated by the extensive underlying genetic heterogeneity. The CMT spectrum of disorders can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The most commonly identified CMT subtypes are CMT1A (PMP22 duplication), CMTX1 (GJB1 mutation), hereditary neuropathy with liability to pressure palsies (PMP22 deletion), CMT1B (MPZ mutation), and CMT2A (MFN2 mutation). Together, these five subtypes account for 92 percent of genetically defined CMT cases. All other CMT subtypes and associated mutations each account for <1 percent of genetically defined CMT. Genetic screening for relatives of a patient diagnosed with CMT is an option, but risk assessment depends on several factors, including accuracy of the diagnosis, determination of the mode of inheritance for the individual family, and results of molecular genetic testing.

Proprietary Testing

Numerous genetic panels are available for the assessment of peripheral neuropathies, such as GeneDx’s panel (64 genes) and Invitae’s panel (83 genes). Other pane’s include ones by Athena Diagnostics (23 genes),MNG Laboratories (139 genes), Prevention Genetics (44 genes), and Variantyx’s Genomic Unity panel (25 genes).

Clinical Utility and Validity

DiVincenzo, et al. (2014) performed an analysis of the genetic landscape of CMT. A total of 14 genes associated with CMT (PMP22, GJB1, MPZ, MFN2, SH3TC2, GDAP1, NEFL, LITAF, GARS, HSPB1, FIG4, EGR2, PRX, and RAB7A) were evaluated out of 3312 individuals. Deletions and duplications in the PMP22 gene consisted of about 78% of positive findings, followed by mutations in the GJB1 (6.7%), MPZ (5.3%), and MFN2 (4.3%) genes. A total of 71% of the pathogenic mutations found were missense mutations. Overall, 95% of the positive results involved one of four genes (PMP22, GJB1, MPZ, MFN2). The authors conclude that these four genes should be screened first before proceeding with further genetic testing.

Pareyson, et al. (2017) reviewed the current literature on CMT diagnosis stating that data justifies a stepwise algorithm considering a variety of factors, such as phenotype, nerve conduction velocities, and ethnicity. The authors note that next-generation sequencing (NGS) is steadily replacing older methods of sequencing in this algorithm. The authors propose evaluating the first few common genes (PMP22, MPZ, et al) and then considering larger sequencing methods such as NGS. However, due to the growing number of genes associated with CMT, these larger sequencing methods may be considered first-line. Finally, the authors state that due to the growing number of associated genes, newer classifications need to be discussed and validated further.

Rudnik-Schöneborn, et al. (2016) evaluated the clinical features and genetic results of 1206 CMT patients and 124 affected relatives. Genetic detection rates were 56% in demyelinating CMT and 17% in axonal CMT. “Three genetic defects (PMP22 duplication/deletion, GJB1/Cx32 or MPZ/P0 mutation) were responsible for 89.3% of demyelinating CMT index patients in whom a genetic diagnosis was achieved, and the diagnostic yield of the three main genetic defects in axonal CMT (GJB1/Cx32, MFN2, MPZ/P0 mutations) was 84.2%.” The authors concluded that “diagnostic algorithms are still useful for cost-efficient mutation detection and for the interpretation of large-scale genetic data made available by next generation sequencing strategies.”

Vaeth, et al. (2019) evaluated the effect of implementing a targeted NGS approach for identifying CMT. The authors stated that from 1992-2012, a total of 1442 CMT analyses were performed (through Sanger sequencing and other quantitative analyses) and a pathogenic variant was discovered in 21.6% of these cases. From this cohort, 195 samples that did not reach a definitive diagnosis were sequenced by a custom 63-gene panel. The authors identified a 5.6% increase in diagnostic yield using this targeted NGS approach.

Cortese, et al. (2020) investigated the effectiveness of NGS panels in CMT. A total of 220 patients were enrolled in the study and a targeted CMT NGS panel was performed. After NGS sequencing, a molecular diagnosis based on a pathogenic variant was found in 30% of the cases and variants of unknown significance were found in 33% of the cases. A total of 39% of the cases held mutations in GJB1, MFN2, and MPZ while the others held mutations in SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, and GARS. Copy number changes were detected in PMP22, MPZ, MFN2, SH3TC2, and FDG4. The authors conclude that "NGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.” 

Rudnik-Schöneborn et al. (2020) Figure 1: Suspected hereditary neuropathy flowchart

Rudnik-Schöneborn, et al. (2020) suggested a diagnostic algorithm for genetic testing of suspected hereditary neuropathy. Advanced genetic sequencing allows for comprehensive evaluation of the pathogenic relevance of identified variants. As shown in the chart above, “If PMP22 copy number analysis is negative, then clinical distinction of HNPP and CMT/dHMN will sort out patients for PMP22 mutation analysis only and those for broader multigene testing. If a pedigree is compatible with X-linked inheritance, it is recommended to analyze coding and non-coding regions of GBJ1. Patients who are tested negative for known neuropathy genes may be included in further whole exome or genome sequencing (WES/WGS) to detect mutations in rare and new genes.”

Yalcintepe, et al. (2021) studied the importance of multiple gene analysis for diagnosis of Charcot Marie Tooth Disease. Fifty-five patients with suspected CMT phenotype were examined using a customized multi-gene panel which was compared to the Multiplex Ligand Probe Amplification method. The custom panel identified 13 cases (7.15%) with a pathogenic/likely pathogenic variant. “The affected genes were MARS1, NDRG1, GJB1, GDAP1, MFN2, PRX, SH3TC2, and FGD4. Six cases (10.9%) had pathogenic variants in GJB1 and FGD4 genes, variants of unknown significance (VUS) in HSPB3, CHRNA1, ARHGEF10, and KIF5A genes. A total of 21 cases (11.55%) had VUS with the genes HSPB3, KIF1B, SCN11A, CHRNA1, HSPB1, FIG4, ARHGEF10, DHTKD1, SBF1, EGR2, SBF2, IGHMBP2, KIF5A, and DNAJB2.” The authors concluded that the NGS customized panel was beneficial, time-saving, and cost-effective in the diagnosis of CMT.

Guidelines and Recommendations

American Academy of Neurology (AAN), the American Academy of Neuromuscular and Electrodiagnostic Medicine (AANEM), and the American Academy of Physical Medicine and Rehabilitation (AAPM&R)

The Polyneuropathy Task Force that included 19 physicians with representatives from the AAN, AANEM, and AAPM&R concluded that “genetic testing is established as useful for the accurate diagnosis and classification of hereditary polyneuropathies (Class I).”

The Task Force stated that “for patients with a cryptogenic polyneuropathy who exhibit a classic hereditary neuropathy phenotype, routine genetic screening may be useful for CMT1A duplication/deletion and Cx32 mutations in the appropriate phenotype (Class III). Further genetic testing may be considered guided by the clinical question.” The Task Force recommended that “genetic testing should be conducted for the accurate diagnosis and classification of hereditary neuropathies (Level A).” The Task Force further recommended that “Genetic testing may be considered in patients with a cryptogenic polyneuropathy and classic hereditary neuropathy phenotype (Level C). 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 [PMP22] duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There is insufficient evidence to support or refute the usefulness of routine genetic testing in cryptogenic polyneuropathy patients without a classic hereditary phenotype (Level U).”

These guidelines were reaffirmed on February 8, 2025.

European Federation of Neurological Societies (EFNS)

The EFNS released recommendations on genetic testing for various types of peripheral neuropathies. Regarding CMT, they noted that “given the rarity of AR CMT in the European population routine diagnostic screening of the many known genes is currently not feasible” but acknowledged that “currently, molecular genetic testing can be offered for several of the more prevalent CMT genes.” EFNS stated that PMP22 duplication should be tested first in patients presenting with CMT1, followed by sequencing of GJB1, MPZ, and PMP22. If a patient presents with CMT2, MFN2 should be screened first, followed by MPZ. If a patient presents with intermediate CMT, GJB1 and MPZ should be screened. EFNS notes that in patients with hereditary neuropathy with liability to pressure palsies will be investigated for a PMP22 deletion at the same time as a screening for a PMP22 duplication.

However, routine diagnostic screenings for hereditary motor neuropathy (HMN) and hereditary sensory-autonomic neuropathy (HSAN) are not feasible due to low mutation frequencies. If screening is performed for these conditions, EFNS recommends BSCL2 as the first candidate for screening in HMN. NTRK1 may also be screened for in congenital insensitivity to pain with anhidrosis patients (CIPA, a sub-phenotype of HSAN) and RAB7 may be screened in CMT2B patients. Finally, SEPT9 may be screened in the context of hereditary neuralgic amyotrophy.

State and Federal Regulations, as applicable

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81324, 81325, 81326, 81403, 81404, 81405, 81406, 81448

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Kang P. Overview of hereditary neuropathies. Updated April 15, 2024. https://www.uptodate.com/contents/overview-of-hereditary-neuropathies

UpToDate. Patient education: Charcot-Marie-Tooth disease (The Basics). https://www.uptodate.com/contents/charcot-marie-tooth-disease-the-basicas 

Kang P. Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis. Updated March 3, 2025. https://www.uptodate.com/contents/charcot-marie-tooth-disease-genetics-clinical-features-and-diagnosis

Bird T. Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. 2025. https://www.ncbi.nlm.nih.gov/books/NBK1358/

NINDS. Charcot-Marie-Tooth Disease. https://www.ninds.nih.gov/health-information/disorders/charcot-marie-tooth-disease 

Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Annals of neurology. Jan 2011;69(1):22-33. doi:10.1002/ana.22166

Züchner S. Charcot-Marie-Tooth Neuropathy Type 2A. 2025. https://www.ncbi.nlm.nih.gov/books/NBK1511/

Schindler A. TRPV4-Associated Disorders. 2020. https://www.ncbi.nlm.nih.gov/books/NBK201366/

Antonellis A, Goldfarb LG, Sivakumar K. GARS-Associated Axonal Neuropathy. 2021. https://www.ncbi.nlm.nih.gov/books/NBK1242/

DeJonghe P, Jordanova AK. Charcot-Marie-Tooth Neuropathy Type 2E/1F. 2011. https://www.ncbi.nlm.nih.gov/books/NBK1187/

Bird T. GDAP1-Related Hereditary Motor and Sensory Neuropathy. 2017. https://www.ncbi.nlm.nih.gov/books/NBK1539/

Hamid Azzedine EL, and Mustafa A Salih. Charcot-Marie-Tooth Neuropathy Type 4C. 2021. https://www.ncbi.nlm.nih.gov/books/NBK1340/

Delague V. Charcot-Marie-Tooth Neuropathy Type 4H. 2013. https://www.ncbi.nlm.nih.gov/books/NBK153601/

Li J. Charcot-Marie-Tooth Neuropathy Type 4J. 2013. https://www.ncbi.nlm.nih.gov/books/NBK169431/

Abrams C. GJB1 Disorders: Charcot Marie Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes. 2024. https://www.ncbi.nlm.nih.gov/books/NBK1374/

Kim J-W, Kim H-J. Charcot-Marie-Tooth Neuropathy X Type 5. 2013. https://www.ncbi.nlm.nih.gov/books/NBK1876/

Bromberg MB. Brachial plexus syndromes. Updated April 4, 2024. https://www.uptodate.com/contents/brachial-plexus-syndromes

Eichler F. Hereditary sensory and autonomic neuropathies. Updated February 17, 2025. https://www.uptodate.com/contents/hereditary-sensory-and-autonomic-neuropathies

Kang P. Charcot-Marie-Tooth disease: Management and prognosis. Updated August 14, 2024. https://www.uptodate.com/contents/charcot-marie-tooth-disease-management-and-prognosis

Charcot-Marie-Tooth News. Genetic Tests and Genetic Counseling. https://charcot-marie-toothnews.com/genetic-tests/

CMTA. Genetic Testing. https://www.cmtausa.org/living-with-cmt/find-help/genetic-testing/

GeneDx. Hereditary Neuropathy Panel. https://www.genedx.com/tests/detail/hereditary-neuropathy-panel-800

Invitae. Invitae Comprehensive Neuropathies Panel. https://www.invitae.com/us/providers/test-catalog/test-03200

Athena Diagnostics. CMT Advanced Evaluation - Comprehensive. https://www.athenadiagnostics.com/view-full-catalog

MNG Laboratories. Charcot-Marie-Tooth Disease, Axonal (NGS Panel and Copy Number Analysis + mtDNA). https://mnglabs.labcorp.com/testing

Prevention Genetics. Charcot-Marie-Tooth (CMT) - Comprehensive Panel. https://www.preventiongenetics.com/testInfo?val=Charcot-Marie-Tooth+%28CMT%29+-+Comprehensive+Panel

DiVincenzo C, Elzinga CD, Medeiros AC, et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Molecular genetics & genomic medicine. Nov 2014;2(6):522-9. doi:10.1002/mgg3.106

Pareyson D, Saveri P, Pisciotta C. New developments in Charcot-Marie-Tooth neuropathy and related diseases. Current opinion in neurology. Oct 2017;30(5):471-480. doi:10.1097/wco.0000000000000474

Rudnik-Schoneborn S, Tolle D, Senderek J, et al. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clinical genetics. Jan 2016;89(1):34-43. doi:10.1111/cge.12594

Vaeth S, Christensen R, Duno M, et al. Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencing platform. Eur J Med Genet. Jan 2019;62(1):1-8. doi:10.1016/j.ejmg.2018.04.003

Cortese A, Wilcox JE, Polke JM, et al. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology. 2020;94(1):e51-e61. doi:10.1212/WNL.0000000000008672

Rudnik-Schöneborn S, Auer-Grumbach M, Senderek J. Charcot-Marie-Tooth disease and hereditary motor neuropathies – Update 2020. Medizinische Genetik. 2020;32(3):207-219. doi:10.1515/medgen-2020-2038

Yalcintepe S, Gurkan H, Dogan IG, et al. The Importance of Multiple Gene Analysis for Diagnosis and Differential Diagnosis in Charcot Marie Tooth Disease. Turk Neurosurg. 2021;31(6):888-895. doi:10.5137/1019-5149.jtn.33661-21.3

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Burgunder JM, Schols L, Baets J, et al. EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders. European journal of neurology. Feb 2011;18(2):207-17. doi:10.1111/j.1468-1331.2010.03069.x

Specialty Matched Consultant Advisory Panel review 7/2019

Medical Director review 7/2019

Specialty Matched Consultant Advisory Panel review 7/2020

Medical Director review 7/2020

Specialty Matched Consultant Advisory Panel review 7/2021

Medical Director review 7/2021

Medical Director review 7/2022

Medical Director review 7/2023

Medical Director review 7/2024

Medical Director review 7/2025

Policy Implementation/Update Information

1/1/2019 BCBSNC will provide coverage for genetic testing for diagnosis of inherited peripheral neuropathies when it is determined to be medically necessary because criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)

8/13/2019 Specialty Matched Consultant Advisory Panel review 7/2019. Medical Director review 7/2019 (jd)

9/10/2019 Reviewed by Avalon 2nd Quarter 2019 CAB. Related Policies added to Description section. When Covered section revised as follows: Item 1, added “or other inherited peripheral neuropathies”; item 2, added “If results indicate a demyelinating neuropathy, then first test for the most commonly identified CMT subtype, CMT1A (PMP22 duplication.”, and removed items a. and b. related to specific values for velocity testing in nerve conduction and specific cascade testing; added item 6 for Genetic testing for Hereditary Motor Neuropathy (HMN) (BSCL2 gene), and added “Note” which refers to policy, General Genetic Testing, Germline Disorders AHS – M2145 for all other uncommon hereditary peripheral neuropathy gene testing. Removed the following statement from the When Not Covered section: “Genetic testing for all other inherited peripheral neuropathies is considered investigational”. Code table removed from the Billing/Coding section and reimbursement statement added. Policy guidelines and references updated. Medical Director review. (jd)

10/29/19 Wording in the Policy, When Covered, and/or Not Covered section(s) changed from Medical Necessity to Reimbursement language, where needed. (hb)

7/28/20 Reviewed by Avalon 2nd Quarter 2020 CAB. Policy guidelines and references updated. Specialty Matched Consultant Advisory Panel review 7/2020. Medical Director review 7/2020. (jd)

8/24/21 Reviewed by Avalon 2nd Quarter 2021 CAB. The following statement was added to the When Not Covered section: “Genetic testing for CMT in asymptomatic individuals is considered investigational.” Background, policy guidelines, and references updated. Specialty Matched Consultant Advisory Panel review 7/2021. Medical Director review 7/2021. (jd)

9/13/22 Reviewed by Avalon 2nd Quarter 2022 CAB. Updated background, guidelines, and references. Billing/Coding section updated. Coverage criteria edited for clarity. No change to policy statement. Medical Director review 7/2022. (tm)

8/15/23 Reviewed by Avalon 2nd Quarter 2023 CAB. Updated Description, Policy Guidelines, and References. The following updates were made to the When Covered section: Former coverage criteria 2 split and expanded into new coverage criteria 1 and 2 for full clarity regarding which genes should be ordered first based on prevalence of cause. Recommendation for genetic counseling removed as coverage criteria and moved into the Policy Description. Removed former coverage criteria 4 (prenatal screening addressed in M2179) and coverage criteria 5 regarding peripheral nerve biopsy. previous Note 1 removed and replaced with new Note 1. Medical Director review 7/2023. (tm)

9/4/24 Reviewed by Avalon 2nd Quarter 2024 CAB. Updated Description, Policy Guidelines, and References. Codes 90640 and S0265 removed from Billing/Coding section, Note 2 under When Covered section updated to reflect changes to definition of a genetic panel within R2162. Now reads: “Note 2: For 2 or more gene tests being run on the same platform, please refer to Laboratory Procedures Medical Policy AHS - R2162.” Medical Director review 7/2024. (tm)

10/15/25 Reviewed by Avalon 3rd Quarter 2025 CAB. Updated Policy Guidelines and References. The following edits were made to the When Covered section for clarity: replaced mutation with “pathogenic or likely pathogenic (P/LP) variants” in coverage criteria 1, 2, 4, 5, Note 1 edited to write out “first”, “second”, and “third” for consistency, Note 2 edited to change “2” to “two”. No change to policy statement. Medical Director review 7/2025. (tm)

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