Test Id : NPPAN

This test includes the option for either one of several predefined panel tests or the option to create a custom gene panel. Pricing for the Custom Gene Panel will be based on the number of genes selected (1, 2-4, 5-14, 15-49, 50-100, and 101-500). See Custom Gene Panel Ordering in Special Instructions.

See Hereditary Peripheral Neuropathy Diagnostic Algorithm in Special Instructions.

The recommended first-tier test to screen for hereditary motor and sensory neuropathy is PMPDD / PMP22 Gene, Large Deletion and Duplication Analysis, Varies, which assesses for large deletions and duplications of the PMP22 gene.

Specimen preferred to arrive within 96 hours of collection.

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube. Do not aliquot.

Additional Information: To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.

• Informed Consent for Genetic Testing
• Hereditary Peripheral Neuropathy Diagnostic Algorithm
• Molecular Genetics: Neurology Patient Information
• Frequently Asked Questions: Custom Gene Ordering Tool
• Custom Gene Panel Ordering
• Informed Consent for Genetic Testing (Spanish)
• Targeted Genes and Methodology Details for Peripheral Neuropathy Gene Panels

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Neurology Patient Information in Special Instructions.

3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.

See Specimen Required

Diagnosis of inherited peripheral neuropathies associated with known causal genes

Serving as a second-tier test for patients in whom previous targeted gene variant analyses for specific inherited peripheral neuropathy-related genes were negative

Identifying variants within genes known to be associated with inherited peripheral neuropathy, allowing for predictive testing of at-risk family members

This ordered service includes the option for one of several peripheral neuropathy related panel tests to be performed. The specific peripheral neuropathy panel requested must be provided in order to perform this test. Testing options include the following:

This test includes the option for either one of several predefined panel tests or the option to create a custom gene panel. Pricing for the Custom Gene Panel will be based on the number of genes selected (1, 2-4, 5-14, 15-49, 50-100, and 101-500). See Custom Gene Panel Ordering in Special Instructions.

See Hereditary Peripheral Neuropathy Diagnostic Algorithm in Special Instructions.

Inherited peripheral neuropathies are a relatively common diverse group of disorders with heterogeneous genetic causes. Due to the considerable overlap in the clinical phenotypes of various neuropathies, it is often difficult to distinguish these specific inherited disorders from sporadic, idiopathic, or acquired forms of neuropathy without genetic testing. Additionally, peripheral neuropathy may be part of an inherited systemic syndromic or metabolic disorder caused by genes in metabolic pathways. Based on the pattern of inheritance and nerve conduction studies, there are 3 major categories of inherited peripheral neuropathies with isolated nerve involvement:

1. Hereditary motor and sensory neuropathy (HMSN), also referred as Charcot Marie Tooth (CMT)

2. Hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy (HSN), if autonomic dysfunction is absent

3. Distal hereditary motor neuropathy (dHMN)

Inherited peripheral neuropathies may also show involvement of the central nervous system (brain or spinal cord), as in hereditary spastic paraplegia (HSP) with neuropathy (complicated form, also referred to as HMSN type 5) or be part of a systemic syndromic or metabolic disorder.

Hereditary Motor and Sensory Neuropathy:

HMSN, or CMT disease, is a major category of inherited peripheral neuropathies and is the most commonly inherited neuromuscular disorder. It is characterized by motor or sensory peripheral nerve involvement. The clinical phenotype is variable and includes wasting and weakness of the distal limb muscles, skeletal deformities, and hearing loss. HMSN/CMT is classified into 5 groups:

1. HMSN 1, which is a dominantly inherited demyelinating form

2. HMSN 2, a dominantly inherited axonal predominant neuropathy

3. HMSN 3 (also called Dejerine-Sottas disease), which is often inherited dominantly with onset in infancy or childhood, is characterized by extremely slow nerve conduction velocities resulting in loss of ambulatory milestones and more generalized neurologic deficit

4. HMSN 4, an autosomal recessive inherited demyelinating form that may also present with extraneural features, including facial dysmorphism and scoliosis, particularly those with HMSN 4C, the most frequent form of HMSN 4

5. HMSN 5, a form associated with spasticity, also known as "complex hereditary spastic paraplegia (HSP)"

Hereditary Motor Neuropathy:

dHMN are one of the major categories of peripheral inherited neuropathies and are characterized by length-dependent, slowly progressive motor neuropathies with variable nerve conduction velocities. The clinical phenotype is variable but includes progressive weakness and atrophy of the distal muscles, foot deformities, and decreased reflexes. There is significant phenotypic overlap with HMSN/CMT; however, sensory loss is usually absent in dHMN. dHMN are subdivided into 11 subtypes based on inheritance pattern and clinical features, and include types 1-7, dHMN plus pyramidal signs, X-linked, congenital distal spinal muscular atrophy, and Jerash type.

Hereditary Sensory and Autonomic Neuropathy:

HSAN, or HSN if autonomic dysfunction is absent, are one of the major categories of inherited peripheral neuropathies. They affect sensory and autonomic nerves and the hallmark feature is the presence of prominent small-fiber involvement. HSAN are subdivided into 5 groups based on age of onset, inheritance pattern, and clinical features:

1. HSAN 1 varieties (HSAN 1A-E) follow an autosomal dominant inheritance pattern with juvenile or adult onset, and severe sensory loss and autonomic dysfunction

2. HSAN 2-5 have an autosomal recessive inheritance pattern and are usually congenital

3. HSAN3, also known as familial dysautonomia or Rilay-Day syndrome, is characterized by prominent autonomic and small-fiber sensory involvement

4. HSAN 4 and 5 are characterized by insensitivity to pain and widespread autonomic disturbance, with HSAN 4 also featuring mental retardation.

Hereditary Spastic Paraplegia:

HSP is characterized by progressive lower extremity weakness and spasticity, and may present with prominent peripheral neuropathy as one of the complicated forms, also known as HMSN type 5. The complicated forms are associated with a variety of other neurological systemic abnormalities and usually follow an autosomal recessive inheritance pattern. The uncomplicated or pure form presents with lower limb weakness and spasticity, and is predominantly characterized by an autosomal dominant inheritance pattern.

SEPT9 Gene, Full Gene Analysis:

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder characterized by periods of severe pain involving the brachial plexus followed by muscle atrophy and weakness. These recurrent episodes can also be accompanied by decreased sensation and paresthesias. Individuals with this disease are generally symptom-free between pain attacks, though many experience lingering effects with repeated attacks. The pain episodes are frequently triggered by physical, emotional, or immunological stress. Less commonly, affected individuals can exhibit non-neurological features including short stature, skin folds, hypotelorism, and cleft palate.

Variants in the SEPT9 gene cause the clinical manifestations of HNA. SEPT9 is currently the only known gene associated with HNA, although approximately 15% of HNA families do not show linkage to this gene.

Given the considerable phenotypic overlap and the broad genetic heterogeneity of inherited peripheral neuropathies a comprehensive diagnostic genetic test is useful to establish the genetic cause in these clinical groups.

An interpretive report will be provided.

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Correlations:

Some individuals who have involvement of 1 or more of the genes on the panel may have a variant that is not identified by the methods performed (eg, large deletions/duplications not targeted, promoter alterations, deep intronic alterations). The absence of a variant, therefore, does not eliminate the possibility of a hereditary peripheral neuropathy disorder. For predictive testing of asymptomatic individuals, it is important to first document the presence of a gene variant in an affected family member.

Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

Technical Limitations:

In some cases, DNA variants of undetermined significance may be identified.

Due to the limitations of next-generation sequencing, small deletions and insertions may not be detected by this test. If a diagnosis of one of the syndromes on this panel is still suspected, contact a molecular genetic counselor at 800-533-1710 for more information regarding follow-up testing options.

Rare alterations exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

In addition to disease-related probes, the multiplex ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.

Evaluation Tools:

Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity clinically is currently not validated.

Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.

Reclassification of Variants-Policy:

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) At this time, it is not standard practice for the laboratory to systematically review “likely pathogenic" alterations or “variants of uncertain significance" that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

1. Richards CS, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

2. Klein CJ, Duan X, Shy ME: Inherited neuropathies: Clinical overview and update. Muscle Nerve. 2013 Oct:48(4):604-622

3. Vallat JM, Mathis S, Funalot B: The various Charcot-Marie-Tooth diseases. Curr Opin Neurol. 2013 Oct;26(5):473-480

4. Rossor AM, Kalmar B, Greensmith L, Reilly MM: The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry. 2012 Jan:83(1):6-14

5. Rotthier A, Baets J, Timmerman V, Janssens K: Mechanisms of disease in hereditary sensory and autonomic neuropathies. Nat Rev Neurol. 2012 Jan:8(2):73-85

6. Finsterer J, Loscher W, Quasthoff S, Wanschitz J, Auer-Grumbach M, Stevanin G: Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J Neurol Sci. 2012 Jul:318(1-2):1-18

7. D'Amico A, Bertini E: Metabolic neuropathies and myopathies. Handb Clin Neurol. 2013;113:1437-1455

• Informed Consent for Genetic Testing
• Hereditary Peripheral Neuropathy Diagnostic Algorithm
• Molecular Genetics: Neurology Patient Information
• Frequently Asked Questions: Custom Gene Ordering Tool
• Custom Gene Panel Ordering
• Informed Consent for Genetic Testing (Spanish)
• Targeted Genes and Methodology Details for Peripheral Neuropathy Gene Panels

Next-generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence a variant in the genes analyzed. See Targeted Genes and Methodology Details for Peripheral Neuropathy Gene Panels in Special Instructions for details regarding the targeted genes for each test.

There may be regions of genes that cannot be effectively amplified and sequenced as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC)-rich content, and repetitive sequences.

Additionally, NGS is used to test for the presence of large deletions and duplications in a subset of genes. See Targeted Genes and Methodology Details for Peripheral Neuropathy Gene Panels in Special Instructions for details regarding the targeted genes analyzed for large deletions and duplications for each test.

Multiplex ligation-dependent probe amplification (MLPA), PCR, and Sanger sequencing is used to confirm alterations detected by NGS when appropriate.(Unpublished Mayo method)

Performed weekly

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• Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
• Prospective clients should contact their Regional Manager. For assistance, contact Customer Service.

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

81448 (if appropriate)

81405 (if appropriate)

81408 (if appropriate)

81407 (if appropriate)

81406 (if appropriate)

81479 (if appropriate)

81325 (if appropriate)

81403 (if appropriate)

81404 (if appropriate)

Sample Reports

Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports

International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports