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Distal Hereditary Motor Neuropathy Sequencing Panel

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
Order Kits
TEST METHODS

NGS Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
1359 AARS 81479 Add to Order
ATP7A 81479
BICD2 81479
BSCL2 81406
DCTN1 81479
DNAJB2 81479
DYNC1H1 81479
FBXO38 81479
GAN 81479
GARS 81406
HINT1 81479
HSPB1 81404
HSPB3 81479
HSPB8 81479
IGHMBP2 81479
LAS1L 81479
REEP1 81405
SETX 81406
SIGMAR1 81479
SLC5A7 81479
SYT2 81479
TRPV4 81479
Full Panel Price* $1740.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1359 Genes x (22) $1740.00 81404, 81405, 81406(x3), 81479(x17) Add to Order
Pricing Comment

If you would like to order a subset of these genes contact us to discuss pricing.

Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Clinical sensitivity cannot be estimated as data do not yet exist. Analytical sensitivity is expected to be high as nearly all pathogenic variants for this disorder are detectable by sequencing. Analytical sensitivity specifically for the IGHMBP2 gene may be lower as gross deletions have been reported.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 AARS$690.00 81479 Add to Order
ATP7A$690.00 81479
BSCL2$690.00 81479
DCTN1$690.00 81479
GAN$690.00 81479
GARS$690.00 81479
HINT1$690.00 81479
HSPB1$690.00 81479
HSPB8$690.00 81479
IGHMBP2$690.00 81479
LAS1L$690.00 81479
REEP1$690.00 81479
SETX$690.00 81479
SLC5A7$690.00 81479
TRPV4$690.00 81479
Full Panel Price* $1290.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (15) $1290.00 81479(x15) Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Clinical sensitivity is expected to be low for these genes because relatively few copy number variations have been reported.

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Clinical Features

Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of disorders characterized by progressive distal motor weakness and atrophy. The weakness is usually greater in the distal lower limbs than the upper limbs, and weakness of the toe extensor muscles is often the presenting sign. Nerve conduction velocities are generally normal in dHMN, and sensory impairment is not a feature of this disorder. Subtypes of dHMN can be differentiated to some extent based on age of onset, pattern of weakness, rate of progression, and appearance of additional complicating features. For discussions on classification, pathophysiology, and molecular genetics of dHMN see Irobi et al. (2004. PubMed ID: 15358725) and Drew et al. (2011. PubMed ID: 21902652).

Genetics

Distal hereditary motor neuropathies can be inherited as autosomal dominant, autosomal recessive, or X-linked conditions. Genes that are involved in dominantly inherited dHMN include AARS, BICD2, DYNC1H1, FBXO38, HSPB1, HSPB3, HSPB8, SETX, GARS, BSCL2, SLC5A7, SYT2, DCTN1, TRPV4, and REEP1. Recessively inherited forms of dHMN are caused by pathogenic variants in the DNAJB2, IGHMBP2, GAN, HINT1 and SIGMAR1 genes. Two X-linked forms are also known (ATP7A and LAS1L).

See individual gene test descriptions for information on molecular biology of gene products.

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for regions not captured or with insufficient number of sequence reads. All reported pathogenic, likely pathogenic, and variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

This panel provides full coverage of all coding exons of the genes listed, plus ~20 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads for coding regions and 0-10 bases of flanking DNA, >10X NGS reads for 11-20 bases of flanking DNA, or Sanger sequencing.

Indications for Test

Individuals with clinical features consistent with distal hereditary motor neuropathy.

Genes

Official Gene Symbol OMIM ID
AARS 601065
ATP7A 300011
BICD2 609797
BSCL2 606158
DCTN1 601143
DNAJB2 604139
DYNC1H1 600112
FBXO38 608533
GAN 605379
GARS 600287
HINT1 601314
HSPB1 602195
HSPB3 604624
HSPB8 608014
IGHMBP2 600502
LAS1L 300964
REEP1 609139
SETX 608465
SIGMAR1 601978
SLC5A7 608761
SYT2 600104
TRPV4 605427
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Amyotrophic Lateral Sclerosis 16, Juvenile AR 614373
Charcot-Marie-Tooth Disease Type 2C AD 606071
Charcot-Marie-Tooth Disease Type 2D AD 601472
Charcot-Marie-Tooth Disease Type 2F AD 606595
Charcot-Marie-Tooth Disease, Axonal, Type 2O AD 614228
Charcot-Marie-Tooth Disease, Type 2L AD 608673
Charcot-Marie-Tooth Disease, Type 2N AD 613287
Distal Hereditary Motor Neuronopathy Type 2A AD 158590
Distal Hereditary Motor Neuronopathy Type 2B AD 608634
Distal Hereditary Motor Neuronopathy Type 5 AD 600794
Giant Axonal Neuropathy AR 256850
Mental Retardation, Autosomal Dominant 13; MRD13 AD 614563
Myasthenic Syndrome, Congenital, 7, Presynaptic AD 616040
Neuromyotonia and axonal neuropathy, autosomal recessive AR 137200
Neuronopathy, Distal Hereditary Motor, Type VIIB AD 607641
Neuronopathy, Distal Hereditary Motor, Type IIC AD 613376
Neuronopathy, Distal Hereditary Motor, Type IID AD 615575
Neuronopathy, Distal Hereditary Motor, Type VB AD 614751
Neuronopathy, Distal Hereditary Motor, Type VIIA AD 158580
Neuropathy, Hereditary Sensory, Type IE AD 614116
Perry Syndrome AD 168605
Scapuloperoneal Spinal Muscular Atrophy AD 181405
Spastic Paraplegia 17 AD 270685
Spinal Muscular Atrophy With Respiratory Distress 1 AR 604320
Spinal Muscular Atrophy, Distal, Autosomal Recessive, 5 AR 614881
Spinal Muscular Atrophy, Distal, Congenital Nonprogressive AD 600175
Spinal Muscular Atrophy, Distal, X-Linked 3 XL 300489
Spinal Muscular Atrophy, Lower Extremity, Autosomal Dominant; SMALED AD 158600
Spinal Muscular Atrophy, Lower Extremity-Predominant, 2 AD 615290
Spinocerebellar Ataxia Autosomal Recessive 1 AR 606002

Related Tests

Name
LAS1L-Related Disorders via the LAS1L Gene
REEP1-Related Disorders via the REEP1 Gene
TRPV4-related Disorders via the TRPV4 Gene
Ataxia with Oculomotor Apraxia Sequencing Panel
Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Autosomal Recessive Spinocerebellar Ataxia and Amyotrophic Lateral Sclerosis Type 4 via the SETX Gene
Charcot Marie Tooth - Axonal Neuropathy Sequencing Panel
Charcot Marie Tooth - Comprehensive Sequencing Panel
Charcot-Marie-Tooth disease, axonal, type 20, Spinal muscular atrophy with lower extremity predominance and Mental retardation, autosomal dominant type 13 via the DYNC1H1 Gene
Complex Hereditary Spastic Paraplegia Sequencing Panel with CNV Detection
Comprehensive Cardiology Sequencing Panel with CNV Detection
Comprehensive Neuromuscular Sequencing Panel
Comprehensive Neuropathy Sequencing Panel
Congenital Generalized Lipodystrophy (CGL) Sequencing Panel
Congenital Myasthenic Syndrome via the SYT2 Gene
Congenital Myopathy Sequencing Panel
Core Myopathy Sequencing Panel
Distal Hereditary Motor Neuropathy, Type 7A via the SLC5A7 Gene
Dynactin-Related Disorders via the DCTN1 Gene
Giant Axonal Neuropathy via the GAN Gene
Glycyl tRNA Synthetase-Related Disorders via the GARS Gene
Heat Shock 22 kDa Protein-Related Disorders via the HSPB8 Gene
Heat Shock 27 kDa Protein-Related Disorders via the HSPB1 Gene
Hereditary Spastic Paraplegia Comprehensive Sequencing Panel with CNV Detection
Menkes Disease and Hereditary Motor Neuropathy via the ATP7A Gene
Peripheral Neuropathies via the HINT1 Gene
Pure Hereditary Spastic Paraplegia Sequencing Panel with CNV Detection
Seipin-Related Disorders via the BSCL2 Gene
Spinal Muscular Atrophy with Respiratory Distress Type 1 via the IGHMBP2 Gene
X-Linked Intellectual Disability Sequencing Panel with CNV Detection

CONTACTS

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Citations
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TEST METHODS

NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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