Nemaline Myopathy via the NEB Exon 55 Deletion
- Summary and Pricing
- Clinical Features and Genetics
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The great majority of tests are completed within 18 days.
This test is intended to detect the exon 55 NEB deletion mutation found in Ashkenazi Jews; it will not detect any other sequence variant. In a world-wide cohort of 355 patients with nemaline myopathy, fourteen probands were found to have the exon 55 deletion mutation and all shared the same ancestral haplotype (Lehtokari et al. Neuromusc Disord 19:179-181, 2009). Sequencing the entire NEB coding region may be indicated in individuals who are clinically affected and have either one or no alleles with the exon 55 deletion. Complete NEB gene sequencing is available from PreventionGenetics (Test #355). Because nemaline myopathy exhibits locus and allelic heterogeneity, a negative NEB test does not rule-out this diagnosis when classic clinical and histological findings are present.
Mutations in the nebulin gene (NEB, OMIM 161650) are one cause of autosomal recessive nemaline myopathy (NEM, OMIM 256030). NEM is a genetically and clinically heterogeneous disorder characterized by muscle weakness, hypotonia and the presence of nemaline bodies in skeletal muscle fibers. Muscle weakness is typically observed in affected neonates or infants, although later onset cases are reported (Ryan et al. Ann Neurol 50:312-320, 2001). The most severely affected muscle groups are proximal limb muscles, facial, bulbar, and respiratory muscles. Deep tendon reflexes are absent or depressed. Histologically, NEM is characterized by type 1 fiber predominance and the presence of rod-like structures called nemaline bodies upon Gomori trichrome staining of skeletal muscle (Ryan et al. Neurol 60:665-673, 2003). Six clinical types of NEM have been delineated based on age of onset, severity and distribution of weakness, and respiratory function (Ryan et al. 2001; North and Ryan. GeneReviews 2010). Nebulin gene mutations more often cause typical neonatal onset disease, although NEB mutations have been found in every clinical form of NEM (Lehtokari et al. Hum Mut 27:946-956, 2006). Overlap among the six clinical groups is significant, and adults are sometimes diagnosed only after another family member has presented with typical signs.
To date, mutations in six genes have been shown to cause nemaline myopathy. Mutations in ACTA1 (NEM3) and NEB (NEM2) are the only relatively common causes (Ryan et al. 2001). All reported cases of NEB-associated NEM have demonstrated autosomal recessive inheritance (Lehtokari et al. 2006). The only common NEB mutation is an exon 55 deletion found at a carrier frequency of about 1% among people of Ashkenazi Jewish ancestry (Anderson et al. Hum Genet 115:185-190, 2004). Much rarer causes of NEM are mutations in TPM3 (NEM1), TPM2 (NEM4), TNNT1 (NEM5), and CFL2 (NEM7).
Testing is accomplished by amplifying patient and control DNAs with PCR primers that flank or lie within the 2,502 bp deletion, essentially as described by Anderson et al. (Hum Genet 115:185-190, 2004). This test permits the identification of patients with normal genotypes, patients who are homozygous for the deletion, and heterozygous carriers.
Indications for Test
Individuals of Ashkenazi Jewish ancestry with symptoms consistent with nemaline myopathy whose muscle biopsies show predominance of type 1 fibers and nemaline bodies.
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- Genetic Counselor Team - email@example.com
- Angela Gruber, PhD - firstname.lastname@example.org
- Anderson SL, Ekstein J, Donnelly MC, Keefe EM, Toto NR, LeVoci LA, Rubin BY. 2004. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 115: 185-190. PubMed ID: 15221447
- Kathryn North, Monique M Ryan (2010). "Nemaline Myopathy."
- Lehtokari VL, Pelin K, Sandbacka M, Ranta S, Donner K, Muntoni F, Sewry C, Angelini C, Bushby K, Van den Bergh P, Iannaccone S, Laing NG, Wallgren-Pettersson C. 2006. Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Hum Mutat 27: 946-956. PubMed ID: 16917880
- Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, Houston R, Muirhead D, Dennett X, Shield LK, Girolami U De, Iannaccone ST, Laing NG, North KN, Beggs AH. 2003. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 60: 665–673. PubMed ID: 12601110
- Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, Laing NG, Beggs AH, North KN. 2001. Nemaline myopathy: a clinical study of 143 cases. Ann. Neurol. 50: 312–320. PubMed ID: 11558787
Targeted Deletion Testing via PCR
See methodology section in the supplemental information included in test reports.
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.