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

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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NextGen Sequencing

Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
3259 DYNC1H1$640.00 81479 Add to Order
Pricing Comments

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

For Sanger Sequencing click here.
Targeted Testing

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

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

Analytical sensitivity may be high because all DYNC1H1 mutations reported to date are expected to be detectable by direct sequencing of genomic DNA. Clinical sensitivity is problematic to predict due to genetic heterogeneity of these disorders and the death of documented cases. Vissers et al. (Nat Genet 42: 1109-1112, 2010) tested exomes of ten patients with unexplained severe intellectual impairment and found one to have a de novo DYNC1H1 mutation. Harms et al. (Neurology 78: 1714-1720, 2012) found two patients with DYNC1H1 mutations among 32 probands with spinal muscular atrophy with lower extremity predominance.

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Clinical Features

DYNC1H1-related disorders are inherited in an autosomal dominant mode. Individuals with Charcot-Marie-Tooth disease type 20 spinal muscular atrophy with lower extremity predominance inherit a DYNC1H1 mutation from an affected parent. Mutations resulting in autosomal dominant mental retardation type 13 have been shown to be de novo (Vissers et al. Nature Genet 42: 1109-1112, 2010; Willemsen et al. J Med Genet 49:179-183, 2012). Missense mutations are the only form of pathogenic gene variant thus far reported for the DYNC1H1 gene.


In a large four generation pedigree affected with type 2 Charcot-Marie-Tooth disease (OMIM 614228) a heterozygous DYNC1H1 missense mutation was found to cosegregate with disease (Weedon et al. Am J Hum Genet 89:308-312, 2011). Some patients presented at birth with club foot or pes cavus and others were reported to require multiple surgeries to correct foot and ankle problems. Other individuals presented early in the second decade of life with abnormal gait, difficulty running, and frequent falls. Still others presented with delayed motor milestones, developmental delays, or speech delays. Common clinical features include proximal and distal lower limb weakness and wasting. Reflexes were reduced in some, but not all affected individuals. Two cases of autosomal dominant mental retardation have been attributed to de novo mutations in the DYNC1H1 gene (OMIM 614563). Both cases were discovered by family-based exome sequencing. The first affected individual had, in addition to severe intellectual disability, hypotonia, hyporeflexia, mild dysmorphic facial features, and broad-based waddling gait with toe-walking (Vissers et al. Nat Genet 42:1109-1112, 2010). The patient was also found to have deficient gyration of the frontal lobes by brain MRI studies. The second case was ascertained at the age of 51years (Willemsen et al. J Med Genet 49:179-183, 2012). This patient also had severe intellectual impairment since infancy and was unable to walk or speak. Additionally, she was mildly dysmorphic and had abnormal cortex structure with deficient gyration. In a large six generation pedigree affected with spinal muscular atrophy with lower extremity predominance (SMALED, OMIM 158600) a heterozygous DYNC1H1 missense mutation was found to cosegregate with disease (Harms et al. Neurology 78:1714-1720, 2012). In affected individuals from this pedigree muscle atrophy and weakness was confined to the lower limbs and there was little progression. Early clinical signs included a waddling gait and awkward running. Deep tendon reflexes were reduced at the knees and nerve conduction studies were consistent with motor neuron disease without sensory involvement. Thirty-two other patients with SMALED were tested by DYNC1H1 sequencing and two were found to have missense mutations. Notably, all three SMALED-causing mutations are located in the tail domain of the DYNC1H1 protein.

Testing Strategy

For this NextGen test, the full coding regions plus ~10 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. 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 any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

Indications for Test

Patients with clinical features of one of the DYNC1H1-related disorders.


Official Gene Symbol OMIM ID
DYNC1H1 600112
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection


Genetic Counselors
  • Harms et al. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.Neurology 78: 1714-1720, 2012. PubMed ID: 22459677
  • Vissers et al. A de novo paradigm for mental retardation. Nature Genet. 42: 1109-1112, 2010. PubMed ID: 21076407
  • Weedon et al. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet 89: 308-312, 2011. PubMed ID: 21820100
  • Willemsen et al. Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects. J Med Genet 49: 179-183, 2012. PubMed ID: 22368300
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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 ~10 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 often covered 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 Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (  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 ~10 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.

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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.
  • 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.


(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.


(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.


(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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