FeedbackMultiplex Ligation-dependent Probe Amplification/Massively Parallel Sequencing
- Recommended test for suspected autosomal dominant or sporadic demyelinating CMT, type 1 (CMT1), or type 1A (CMT1A).
- Deletion/duplication of PMP22 gene is performed first. If no large deletions or duplications are detected, sequencing of hereditary neuropathy genes is performed (see Genes Tested table for gene list).
- Deletion/duplication analysis is also orderable separately; see below.
Multiplex Ligation-dependent Probe Amplification
- Recommended test for suspected HNPP, appropriate first-tier test for suspected autosomal dominant or sporadic demyelinating CMT, CMT1, or CMT1A; does not detect sequence variants.
- Recommended test if there is a known familial PMP22 deletion or duplication previously identified in a family member. A copy of the family member’s test result documenting the known familial variant is required.
Polymerase Chain Reaction/Sequencing
- Recommended test for a known familial sequence variant previously identified in a family member.
- A copy of the family member’s test result documenting the known familial variant is required.
Charcot-Marie-Tooth (CMT) hereditary neuropathy is a group of disorders that involve chronic motor and sensory polyneuropathy, also referred to has hereditary motor and sensory neuropathy (HMSN). There are many types and subtypes with overlapping symptoms, which makes it difficult to distinguish between them. A combination of phenotype, family history, nerve conduction velocity (NCV), electromyography (EMG) and genetic testing to identify the causative gene/variant is used to differentiate the various types and subtypes of CMT and HMSN. Molecular testing for these conditions can be performed to confirm the diagnosis in symptomatic individuals or to identify family members at risk for developing the condition. Additionally, nongenetic or acquired etiologies should be excluded.
Disease Overview
Prevalence of CMT hereditary neuropathy: 1/3,300
Age of onset: First through third decade
| Disorder | Common Symptom(s) |
|---|---|
|
CMT |
Progressive distal motor and sensory neuropathy Muscle weakness/atrophy Pes cavus foot deformity, foot drop |
|
HSN/HSAN |
Predominant sensory neuropathy with motor involvement in advanced disease |
|
HMN |
Distal motor neuropathy without sensory loss |
|
HNPP |
Transient/recurring focal pressure neuropathies (eg, carpal tunnel syndrome) Mild to moderate peripheral neuropathy |
| HMN, hereditary motor neuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathies; HSN, hereditary sensory neuropathies | |
Test Interpretation
See Genes Tested table for genes included in the panel.
Clinical Sensitivity
| Test | Clinical Sensitivity |
|---|---|
|
PMP22 deletion/duplication analysis |
70-80% for CMT1 80% for HNPP |
|
Multigene sequencing panel |
Clinical sensitivity is disorder dependent |
| Source: Bird; Opal | |
Analytic Sensitivity
- For multiplex ligation-dependent probe amplification (MLPA): 99%
- For massively parallel sequencing, refer to the following table.
| Variant Class | Analytic Sensitivity (PPA) Estimatea (%) | Analytic Sensitivity (PPA) 95% Credibility Regiona (%) |
|---|---|---|
|
SNVs |
99.2 |
96.9-99.4 |
|
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
|
Deletions 11-44 bp |
100 |
87.8-100 |
|
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
|
Insertions 11-23 bp |
100 |
62.1-100 |
|
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Results
| Result | Variant(s) Detected | Clinical Significance |
|---|---|---|
|
Positive |
Heterozygous: One pathogenic or likely pathogenic variant detected in an autosomal or X-linked dominant gene |
Confirms a diagnosis of a hereditary neuropathy |
|
Homozygous/compound heterozygous: Two pathogenic or likely pathogenic variants detected in a autosomal recessive gene |
Confirms a diagnosis of a hereditary neuropathy |
|
|
Heterozygous: One pathogenic or likely pathogenic variant detected in an autosomal or X-linked recessive gene |
Confirms carrier status for hereditary neuropathy; some females may exhibit symptoms depending on the gene/disorder |
|
|
Uncertain |
One or more variant(s) of uncertain significance detected |
Unknown if variant(s) are disease-causing or benign |
|
Negative |
No pathogenic variant detected |
Likelihood of hereditary neuropathy diagnosis is reduced, but not excluded |
Limitations
- A negative result does not exclude a heritable form of neuropathy.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the targeted genes
- Regulatory region variants and deep intronic variants
- Breakpoints of large deletions/duplications in PMP22
- Large deletions/duplications in genes other than PMP22
- Noncoding transcripts
- The following exons are not sequenced due to technical limitations of the assay:
- SPTLC1 (NM_006415) 3
- DNMT1 (NM_001130823) 5
- SETX (NM_001351528) 26
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants
Genes Tested
| Gene | MIM Number | Disorder and Subtype (Abbreviation) | Inheritance |
|---|---|---|---|
|
AARS |
601065 |
CMT disease, axonal, type 2N (CMT 2N) |
AD |
|
AIFM1 |
300169 |
Cowchock syndrome (CMT X4) |
XL |
|
ATL1 |
606439 |
Spastic paraplegia 3A, autosomal dominant (SPG 3A) Neuropathy, hereditary sensory, type ID (HSN 1D) |
AD |
|
ATP7A |
300011 |
Menkes disease Occipital horn syndrome Spinal muscular atrophy, distal, X-linked 3 |
XL |
|
BAG3 |
603883 |
Myopathy, Myofibrillar, 6 Giant axonal neuropathy |
AD |
|
BICD2 |
609797 |
Spinal muscular atrophy, lower extremity-predominant, 2 |
AD |
|
BSCL2 |
606158 |
BSCL2-related neurologic disorders/seipinopathy neuropathy, distal hereditary motor, type VA (dHMN/HMN 5A) Silver spastic paraplegia syndrome CMT disease type 2 (CMT2) |
AD |
|
CCT5 |
610150 |
Neuropathy, hereditary sensory, with spastic paraplegia (HSN with SPG) |
AR |
|
DCTN1 |
601143 |
Neuropathy, distal hereditary motor, type VIIB (dHMN 7B) Perry syndrome |
AD |
|
DHTKD1 |
614984 |
CMT disease type 2Q (CMT 2Q) |
AD |
|
DNAJB2 |
604139 |
Spinal muscular atrophy, distal, autosomal recessive, 5 |
AR |
|
DNM2 |
602378 |
CMT disease, axonal type 2M (CMT 2M) CMT disease, dominant intermediate B (DI-CMT B) Centronuclear myopathy 1 |
AD |
|
DNMT1 |
126375 |
Neuropathy, hereditary sensory, type IE (HSAN 1E) Cerebellar ataxia, deafness, and narcolepsy |
AD |
|
DYNC1H1 |
600112 |
CMT disease, axonal, type 2O (CMT 2O) Spinal muscular atrophy, lower extremity-predominant 1 |
AD |
|
EGR2 |
129010 |
CMT disease, type 1D (CMT 1D) |
AD |
|
Dejerine-Sottas disease Neuropathy, congenital hypomyelinating, 1 (CMT 4E) |
AD or AR |
||
|
ELP1 (IKBKAP) |
603722 |
Familial dysautonomia Hereditary sensory and autonomic neuropathy type III (HSAN 3) |
AR |
|
FBLN5 |
604580 |
Neuropathy, hereditary, with or without age-related macular degeneration |
AD |
|
FGD4 |
611104 |
CMT disease, type 4H (CMT 4H) |
AR |
|
FIG4 |
609390 |
CMT disease, type 4J (CMT 4J) |
AR |
|
Amyotrophic lateral sclerosis 11 |
AD |
||
|
GAN |
605379 |
Giant axonal neuropathy-1 |
AR |
|
GARS |
600287 |
CMT disease, type 2D (CMT 2D) Neuropathy, distal hereditary motor, type VA (dHMN 5A) |
AD |
|
GDAP1 |
606598 |
CMT disease, type 4A (CMT 4A) CMT disease, axonal, with vocal cord paresis CMT disease, axonal, type 2K (CMT 2K) CMT disease, recessive intermediate, A (RI-CMT A) |
AR |
|
GJB1 |
304040 |
CMT neuropathy, X-linked dominant, 1 (CMT X1) |
XL |
|
GNB4 |
610863 |
CMT disease, dominant intermediate F (DI-CMT 1F) |
AD |
|
HARS |
142810 |
CMT disease, axonal, type 2W (CMT 2W) |
AD |
|
HEXA |
606869 |
Tay-Sachs disease/ hexosaminidase A deficiency |
AR |
|
HINT1 |
601314 |
Neuromyotonia and axonal neuropathy |
AR |
|
HOXD10 |
142984 |
Isolated congenital vertical talus |
AD |
|
HSPB1 |
602195 |
CMT disease, axonal, type 2F (CMT 2F) Neuropathy, distal hereditary motor, type IIB; (dHMN 2B) |
AD |
|
HSPB3 |
604624 |
Neuronopathy, distal hereditary motor, type IIC (dHMN 2C) |
AD |
|
HSPB8 |
608014 |
CMT disease, axonal, type 2L (CMT 2L) Neuropathy, distal hereditary motor, type IIA (dHMN 2A) |
AD |
|
IGHMBP2 |
600502 |
Neuronopathy, distal hereditary motor, type VI (HMN 6) Charcot-Marie-Tooth disease, axonal, type 2S (CMT 2S) |
AR |
|
INF2 |
610982 |
CMT disease, dominant intermediate E (DI-CMT E) |
AD |
|
KARS |
601421 |
CMT disease, recessive intermediate, B (RI-CMT B) |
AR |
|
KIF1A |
601255 |
Neuropathy, hereditary sensory, type IIC (HSAN 2C SPG 30) |
AR |
|
KIF1B |
605995 |
CMT disease, type 2A1 (CMT 2A1) |
AD |
|
KIF5A |
602821 |
SPG 10 |
AD |
|
LAS1L |
300964 |
Spinal muscular atrophy with respiratory distress (SMARD) |
XL |
|
LITAF |
603795 |
CMT disease, type 1C (CMT 1C) |
AD |
|
LMNA |
150330 |
CMT disease, type 2B1 (CMT 2B1) |
AR |
|
LRSAM1 |
610933 |
CMT disease, axonal, type 2P (CMT 2P) |
AD or AR |
|
MARS |
156560 |
CMT disease, axonal, type 2U (CMT 2U) |
AD |
|
MED25 |
610197 |
CMT disease, type 2B2 (CMT 2B2) |
AR |
|
MFN2 |
608507 |
Hereditary motor and sensory neuropathy VIA (HMSN 6A) CMT disease, axonal, type 2A2A (CMT 2A2A) |
AD |
|
CMT disease, axonal, type 2A2B (CMT 2A2B) |
AR |
||
|
MORC2 |
616661 |
CMT disease, axonal, type 2Z (CMT 2Z) |
AD |
|
MPZ |
159440 |
CMT disease, dominant intermediate D (DI-CMT D) CMT disease, type 1B (CMT 1B) CMT disease, type 2I (CMT 2I) CMT disease, type 2J (CMT 2J) Roussy-Levy syndrome |
AD |
|
Neuropathy, congenital hypomyelinating (CMT 4) Dejerine-Sottas disease |
AD or AR |
||
|
MTMR2 |
603557 |
CMT disease, type 4B1 (CMT 4B1) |
AR |
|
NDRG1 |
605262 |
CMT disease, type 4D (CMT 4D) |
AR |
|
NEFL |
162280 |
CMT disease, type 2E (CMT 2E) CMT disease, dominant intermediate G (DI-CMT G) |
AD |
|
CMT disease, type 1F (CMT 1F) |
AD or AR |
||
|
NGF |
162030 |
Neuropathy, hereditary sensory and autonomic, type V (HSAN 5) |
AR |
|
NTRK1 |
191315 |
Insensitivity to pain, congenital, with anhidrosis (HSAN 4) |
AR |
|
PDK3 |
300906 |
CMT disease, X-linked dominant, 6 (CMT X6) |
XL |
|
PLEKHG5 |
611101 |
CMT disease, recessive intermediate C (RI-CMT C) Spinal muscular atrophy, distal, autosomal recessive, 4 |
AR |
|
PMP22 |
601097 |
CMT disease, type 1A (CMT 1A) (Gene duplication) Neuropathy, recurrent, with pressure palsies (HNPP) (Gene deletion and sequence variants) CMT disease, type 1E (CMT 1E) (Sequence variants) |
AD |
|
PRNP |
176640 |
Hereditary prion diseases |
AD |
|
PRPS1 |
311850 |
CMT disease, X-linked recessive, 5 (CMT X5) |
XL |
|
PRX |
605725 |
CMT disease, type 4F (CMT 4F) |
AR |
|
RAB7A |
602298 |
CMT disease, type 2B (CMT 2B) |
AD |
|
REEP1 |
609139 |
Neuronopathy, distal hereditary motor, type VB (dHMN 5B) Spastic paraplegia 31, autosomal dominant |
AD |
|
RETREG1 (FAM134B) |
613114 |
Neuropathy, hereditary sensory and autonomic, type IIB (HSAN 2B) |
AR |
|
SBF1 |
603560 |
CMT disease, type 4B3 (CMT 4B3) |
AR |
|
SBF2 |
607697 |
CMT disease, type 4B2 (CMT 4B2) |
AR |
|
SCN9A |
603415 |
Small fiber neuropathy Paroxysmal extreme pain disorder |
AD |
|
Hereditary sensory and autonomic neuropathy type IID (HSAN 2D) Insensitivity to pain, congenital |
AR |
||
|
SETX |
608465 |
Amyotrophic lateral sclerosis 4, juvenile |
AD |
|
Spinocerebellar ataxia, autosomal recessive 1 |
AR |
||
|
SH3TC2 |
608206 |
Mononeuropathy of the median nerve, mild |
AD |
|
CMT disease, type 4C (CMT 4C) |
AR |
||
|
SLC12A6 |
604878 |
Agenesis of the corpus callosum with peripheral neuropathy |
AR |
|
SLC5A7 |
608761 |
Neuronopathy, distal hereditary motor, type VIIA (dHMN 7A) |
AD |
|
SPTLC1 |
605712 |
Neuropathy, hereditary sensory and autonomic, type IA (HSAN 1A) |
AD |
|
SPTLC2 |
605713 |
Neuropathy, hereditary sensory and autonomic, type IC (HSAN 1C) |
AD |
|
TDP1 |
607198 |
Spinocerebellar ataxia, autosomal recessive with axonal neuropathy |
AR |
|
TFG |
602498 |
Hereditary motor and sensory neuropathy, Okinawa type |
AD |
|
TRIM2 |
614141 |
CMT disease, type 2R (CMT 2R) |
AR |
|
TRPV4 |
605427 |
Hereditary motor and sensory neuropathy, type IIC (HMSN 2C) |
AD |
|
TTR |
176300 |
Amyloidosis, hereditary, transthyretin-related Carpal tunnel syndrome, familial |
AD |
|
WNK1 |
605232 |
Neuropathy, hereditary sensory and autonomic, type II (HSAN 2A) |
AR |
|
YARS |
603623 |
CMT disease, dominant intermediate C (DI-CMT C) |
AD |
|
AD, autosomal dominant; AR, autosomal recessive; dHMN/HMN, (distal) hereditary motor neuropathy; DI-CMT, dominant-intermediate CMT; HMSN, hereditary motor and sensory neuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathy; HSN, hereditary sensory neuropathy; RI-CMT, recessive-intermediate CMT; SPG, spastic paraplegia; XL, X-linked |
|||
References
-
GeneReviews - Charcot-Marie-Tooth Hereditary Neuropathy Overview
Bird TD. Charcot-Marie-Tooth (CMT) hereditary neuropathy overview. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2021. [Last revision: Sep 2021; Accessed: Sep 2021]
-
GeneReviews - GAN-related neurodegeneration
Opal P. GAN-relatead neurodegeneration. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last update: Oct 2021; Accessed: Nov 2021]
GeneReviews: GJB1 disorders: Charcot-Marie-Tooth neuropathy
Abrams CK. GJB1 disorders: Charcot-Marie-Tooth neuropathy (CMT1X) and central nervous system phenotypes. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last update: Feb 2020; Accessed: Nov 2021]
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Auer-Grumbach M, Weger M, Fink-Puches R, et al. Fibulin-5 mutations link inherited neuropathies, age-related macular degeneration and hyperelastic skin. Brain. 2011;134(Pt 6):1839-1852.
GeneReviews - Hereditary Neuropathy with Liability to Pressure Palsies
Chrestian N. Hereditary neuropathy with liability to pressure palsies. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2021. [Last update: Aug 2020; Accessed: Nov 2021]
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Claeys KG, Züchner S, Kennerson M, et al. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain. 2009;132(Pt 7):1741-1752.
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Dierick I, Baets J, Irobi J, et al. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. Brain. 2008;131(Pt 5):1217-1227.
GeneReviews - Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum
Gauvreau C, Brisson JD, Dupré N. Hereditary motor and sensory neuropathy with agenesis of the corpus callosum. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2021. [Last update: Sep 2020; Accessed: Nov 2021]
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Rossor AM, Polke JM, Houlden H, et al. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol. 2013;9(10):562-571.