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Emery-Dreifuss Muscular Dystrophy (EDMD1) via the EMD Gene

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

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
592 EMD$550.00 81405 Add to Order
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 18 days.

Clinical Sensitivity
EMD gene sequencing is reported to detect ~99% of individuals who have all three major clinical symptoms, have established X-linked inheritance, and have absent emerin by western blot or immunohistocytochemistry (Manilal et al. Hum Mol Genet 7:855–864, 1998).  EMD is the most common cause of X-linked EDMD, but over-all EMD is less common than autosomal dominant EDMD caused by LMNA mutations.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 EMD$690.00 81404 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 Features

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous disorder characterized by: 1) joint contractures with early childhood onset, 2) slowly progressing muscle weakness and wasting and 3) cardiac conduction defects. Typically, the presenting symptom of X-linked EDMD is joint contractures of elbows, Achilles tendon, and post cervical muscles. Loss of ambulation may result from severe contractures of the spine and lower limbs, but is rare in X-linked EDMD. Muscle weakness and wasting is slowly progressive until after the third decade of life. The initial muscle groups affected follow a humero-peroneal distribution and scapular and pelvic girdle muscles become affected later in the course of the disease. The presenting clinical signs of muscle weakness include toe-walking and a waddling gait. Cardiac conduction defects are the most severe manifestation of EDMD, and female carriers without signs of skeletal muscle weakness or of contractures have been reported with cardiac disease (Emery. J Med Genet 26:637-641, 1989; Buckley et al. Heart 82:105-108, 1999). Cardiac disease can present in teenagers and includes conduction defects, dilated cardiomyopathy, and infiltration of the myocardium by fibrous and adipose tissue (Buckley et al. Heart 82:105-108, 1999). Serum CK levels are moderately elevated, most commonly in the early stages of disease (Bonne et al. Ann Neurol. 48:170–180, 2000). Age of onset and disease severity demonstrate both inter-and intra-familial variability (Mercuri et al. Neurology 54:1704–1705, 2000).

Genetics

Emery-Dreifuss muscular dystrophy can be inherited as an autosomal dominant disorder secondary to mutations in LMNA, SYNE1 or SYNE2; as an autosomal recessive disorder secondary to LMNA mutations; or as an X-linked recessive disorder secondary to FHL1 or EMD mutations. EMD (OMIM 300384) encodes emerin, an inner nuclear membrane-localized protein with a role in membrane anchorage to the cytoskeleton through association with lamin A (Bione et al. Proc Natl Acad Sci USA 90:10977-10981, 1993). Immunostaining of muscle biopsy from most EDMD1 patients shows complete absence of emerin. Consistent with this finding, the majority of pathogenic variants in EMD are nonsense mutations, small out-of-frame insertions and deletions, splice site mutations, and gross deletions.

Testing Strategy

Emerin is coded by exons 1-6 of the EMD gene located on chromosome Xq28. Testing is accomplished by amplifying each coding exon and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

Indications for Test

Individuals with symptoms consistent with Emery-Dreifuss muscular dystrophy and X-linked recessive inheritance.

Gene

Official Gene Symbol OMIM ID
EMD 300384
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Emery-Dreifuss Muscular Dystrophy 1, X-Linked 310300

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Bione, S., et.al. (1993). "Transcriptional organization of a 450-kb region of the human X chromosome in Xq28." Proc Natl Acad Sci U S A 90(23): 10977-81. PubMed ID: 8248200
  • Bonne, G., et.al. (2000). "Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene." Ann Neurol 48(2): 170-80. PubMed ID: 10939567
  • Buckley A, Dean J, Mahy I. 1999. Cardiac involvement in Emery Dreifuss muscular dystrophy: a case series. Heart 82: 105–108. PubMed ID: 10377322
  • Emery, A. E. (1989). "Emery-Dreifuss syndrome." J Med Genet 26(10): 637-41. PubMed ID: 2685312
  • Manilal, S., et.al. (1998). "Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression." Hum Mol Genet 7(5): 855-64. PubMed ID: 9536090
  • Mercuri, E., et.al. (2000). "Early and severe presentation of autosomal dominant Emery-Dreifuss muscular dystrophy (EMD2)." Neurology 54(8): 1704-5. PubMed ID: 10762524
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all 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 for example 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 and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

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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