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Test Code DWPAN Comprehensive Distal Weakness Gene Panel, Varies


Ordering Guidance


Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

 

Customization of this panel and single gene analysis for any gene present on this panel are available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.



Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Specimen Required


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: 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 whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred)/Refrigerated

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.


Forms

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:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Molecular Genetics: Neurology Patient Information

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

Secondary ID

617545

Useful For

Establishing a molecular diagnosis for patients with distal weakness

 

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

Method Name

Sequence Capture and Next-Generation Sequencing (NGS), Polymerase Chain Reaction (PCR), Sanger Sequencing, and Dosage Analysis by Droplet Digital Polymerase Chain Reaction (ddPCR)

Reporting Name

Distal Weakness Gene Panel

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

Peripheral neuropathy and distal myopathy are well-established inherited neuromuscular disorders characterized by progressive weakness and atrophy of the distal limb muscles.

 

Inherited peripheral neuropathies are common neurologic disorders that represent a spectrum of diseases with different etiologies. Based on the pattern of inheritance and nerve conduction studies, there are 3 major categories of inherited peripheral neuropathies with isolated nerve involvement. The first group is hereditary motor and sensory neuropathy, also referred to as Charcot-Marie-Tooth (CMT) disease. Individuals with CMT typically present with slowly progressive muscle weakness and atrophy primarily affecting the distal extremities. The second group is hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy if autonomic dysfunction is absent. They predominantly feature slowly progressive loss of multimodal sensation and autonomic dysfunction, with the most common features of HSANs being the loss of sensation of pain and temperature. The third group is distal hereditary motor neuropathy, which is characterized by length-dependent lower motor neuron dysfunction. The clinical phenotype is variable but includes progressive weakness and atrophy of the distal muscles, foot deformities, and decreased reflexes. Inherited peripheral neuropathies may also show involvement of the central nervous system (brain or spinal cord), as in hereditary spastic paraplegia with neuropathy or be part of a systemic syndromic or metabolic disorder. It is important to note that this assay includes testing for TTR-associated with familial amyloidosis.

 

Distal myopathies are characterized by distal weakness and atrophy that starts in the muscles of the hands or feet and lack of cranial involvement or sensory loss. Distal myopathies are classified based on clinical features, inheritance pattern, and histopathological findings, such as the presence of rimmed vacuoles. Categories of distal myopathies include late adult-onset autosomal dominant forms, adult-onset autosomal dominant forms, early-onset autosomal dominant forms, early-onset autosomal recessive forms, and early adult-onset autosomal recessive forms. Additionally, inclusion body myositis presents with distal muscle weakness and may be in the differential with the distal myopathies.

 

Given the considerable overlap in clinical phenotype of various disorders with distal weakness, multigene panels can be an efficient and cost-effective way to establish a molecular diagnosis.

Reference Values

An interpretive report will be provided.

Interpretation

All detected variants 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.

Cautions

Clinical Correlations:

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

 

If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

 

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact the Mayo Clinic Laboratories genetic counselors at 800-533-1710.

 

Technical Limitations:

Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.

 

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.

 

This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.

 

Deletion/Duplication Analysis:

This analysis targets single and multi-exon deletions/duplications; however, in some instances single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.

 

This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.

 

Genes may be added or removed based on updated clinical relevance. For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.

 

If the patient has had an allogeneic hematopoietic stem cell transplant or a recent blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.

 

Reclassification of Variants:

Currently, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages healthcare providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time. Due to broadening genetic knowledge, it is possible that the laboratory may discover new information of relevance to the patient. Should that occur, the laboratory may issue an amended report.

 

Variant Evaluation:

Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(1) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

 

Rarely, incidental or secondary findings may implicate another predisposition or presence of active disease. These findings will be carefully reviewed to determine whether they will be reported.

Clinical Reference

1. Richards S, 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. 201517(5):405-424

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

3. Udd B: Distal myopathies. Curr Neurol Neurosci Rep. 2014;14(3):434. doi:10.1007/s11910-013-0434-4

4. Savarese M, Sarparanta J, Vihola A, et al: Panorama of the distal myopathies. Acta Myol. 2020;39(4):245-265. doi:10.36185/2532-1900-028

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletion/insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction (PCR)-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

 

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. See Targeted Genes and Methodology Details for Comprehensive Distal Weakness Gene Panel for details regarding the targeted genes analyzed for each test and specific gene regions not routinely covered.(Unpublished Mayo method)

 

Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

 

Droplet digital PCR is performed for detection and quantification of SMN1 exon 7 and SMN2 exon 7 associated with spinal muscular atrophy.

 

Genes analyzed: AAAS, AARS1, ABCA1, ABCD1, ACTA1, AIFM1, ALDH18A1, AMACR, ANO5, AP5Z1, APOA1, APTX, ARSA, ATL1, ATL3, ATM, ATP1A1, ATP7A, B4GALNT1, BAG3, BICD2, BIN1, BSCL2, C12orf65 (MTRFR), C1orf194, CAV3, CHCHD10, CLCF1, CLTCL1, CNTNAP1, COQ4, COQ7, COX10, COX20, COX6A1, CPOX, CRLF1, CRYAB, CTDP1, CYP27A1, CYP2U1, CYP7B1, DCTN1, DDHD1, DES, DGAT2, DHH, DNAJB2, DNAJB6, DNM2, DNMT1, DST, DYNC1H1, DYSF, EGR2, ELP1, ERCC8, FA2H, FAM126A, FBLN5, FBXO38, FDX2, FGD4, FGF14, FHL1, FIG4, FLNC, FLVCR1, FMR1, FXN, GALC, GAN, GARS1, GBA2, GBE1, GBF1, GDAP1, GJB1, GLA, GM2A, GNB4, GNE, GSN, HADHA, HADHB, HARS1, HEXA, HEXB, HINT1, HK1, HMBS, HNRNPA1, HNRNPA2B1, HSPB1, HSPB8, HSPD1, IARS2, IBA57, IGHMBP2, INF2, KARS1, KIF1A, KIF5A, LAMA2, LDB3, LITAF, LMNA, LRSAM1, MARS1, MATR3, MCM3AP, MFN2, MME, MORC2, MPC1, MPV17, MPZ, MTMR2, MTTP, MYH14, MYH2, MYH7, MYOT, NAGLU, NDRG1, NEB, NEFH, NEFL, NF2, NGF, NIPA1, NTRK1, OPA1, PDK3, PDYN, PEX7, PHYH, PLA2G6, PLEKHG5, PLP1, PMP2, PMP22, PNKP, PNPLA6, POLG, PPOX, PRDM12, PRKCG, PRNP, PRPS1, PRX, PTRH2, RAB7A, REEP1, RETREG1, RNASEH1, RRM2B, RTN2, SACS, SBF1, SBF2, SCN10A, SCN11A, SCN9A, SCO2, SELENON, SEPTIN9, SETX, SH3TC2, SIGMAR1, SLC12A6, SLC25A19, SLC25A46, SLC52A2, SLC52A3, SLC5A7, SNAP29, SOD1, SORD, SOX10, SPAST, SPG11, SPG21, SPG7, SPTAN1, SPTLC1, SPTLC2, SQSTM1, SUCLA2, SURF1, TDP1, TFG, TIA1, TRIM2, TRPV4, TSFM, TTN, TTPA, TTR, TUBB3, TWNK, TYMP, UBA1, VCP, VPS13D, VRK1, VWA1, WARS1, WASHC5, WNK1, YARS1, and ZFYVE26

Day(s) Performed

Varies

Report Available

28 to 42 days

Specimen Retention Time

Whole blood: 2 weeks (if available); Extracted DNA: 3 months

Performing Laboratory

Mayo Clinic Laboratories in Rochester

Test Classification

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

CPT Code Information

81443

LOINC Code Information

Test ID Test Order Name Order LOINC Value
DWPAN Distal Weakness Gene Panel 103731-6

 

Result ID Test Result Name Result LOINC Value
617546 Test Description 62364-5
617547 Specimen 31208-2
617548 Source 31208-2
617549 Result Summary 50397-9
617550 Result 82939-0
617551 Interpretation 69047-9
618178 Additional Results 82939-0
617552 Resources 99622-3
617553 Additional Information 48767-8
617554 Method 85069-3
617555 Genes Analyzed 48018-6
617556 Disclaimer 62364-5
617557 Released By 18771-6

Testing Algorithm

For more information see Hereditary Peripheral Neuropathy Diagnostic Algorithm