Congenital Myasthenic Syndromes and Lethal Multiple Pterygium Syndrome via the CHRNA1 Gene
Summary and Pricing
Test Method
Exome Sequencing with CNV DetectionTest Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
---|---|---|---|---|---|
8539 | CHRNA1 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
The Sanger Sequencing method for this test is NY State approved.
For Sanger Sequencing click here.Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or postsynaptic proteins. CMS are characterized by fatigable weakness affecting limb, ocular, facial, and bulbar muscles. Neonates present with feeding problems, choking, feeble cry, and muscle weakness. Patients presenting in later childhood are seen with abnormal exercise-induced fatigue and difficulty running. Most patients present prior to 2 years of age although rare exceptions are reported (eg. Croxen et al. Neurol 59:162-168, 2002). Symptoms are extremely variable and are in some cases induced by febrile illness, infection, or excitement (eg. Byring et al. Neuromuscul Disord 12:548-553, 2002). Life-threatening respiratory crises may occur in affected neonates or older children. CMS may be differentiated from myasthenia gravis, an acquired autoimmune disorder, by earlier age at onset and by negative serology tests for anti-acetylcholine receptor (AchR) and anti-Musk antibodies. Lethal multiple pterygium syndrome (LMPS, OMIM 253290) is characterized by prenatal growth deficiency, contractures, pterygia, and dysmorphic facies. Joint contractures and multiple pterygia are universal findings. Pulmonary hypoplasia is likely the primary cause of mortality. Contractures are found at the elbows, knees, hips, shoulders, hands, and feet. Pterygia are found between the chin and sternum as well as the popliteal, axillary, antecubital, and ankle areas. Facial features include ocular hypertelorism, epicanthal folds, small chin and mouth, and low-set ears.
Genetics
Abnormalities of proteins involved with neuromuscular transmission underlie CMS, limb girdle CMS, Pena-Shokeir syndrome, and multiple pterygium syndromes. These disorders, which may represent a phenotypic continuum of a single entity, are most often inherited in an autosomal recessive manner. CHRNA1 gene variants have been found in patients with fast and slow channel CMS (Engel and Sine Curr Opinion in Pharmacol 5:308-321, 2005). Fast channel CMS (OMIM 608930) secondary to loss-of-function variants in the acetylcholine receptor alpha gene (CHRNA1, OMIM 100690) is mostly inherited as a recessive condition (Ohno et al. Neuron 17:157-170, 1996; Wang et al. Nature Neurosci 2:226-233, 1999). However, dominant inheritance of CHRNA1-related fast channel CMS has been reported (Webster et al. Neurol 62:1090-1096, 2004). Slow-channel CMS (OMIM 601462) secondary to gain-of-function variants in the CHRNA1 gene is inherited as a dominant condition (Engel et al. Hum Molec Genet 5:1217-1227, 1996; Shen et al. Ann Neurol 60:128-136, 2006). Lethal multiple pterygium syndrome is inherited as an autosomal recessive condition (Michalk et al. Am J Hum Genet 82:464-476, 2008). Null and low expressor CHRNA1 variants in the homozygous or compound heterozygous state lead to CMS with end-plate AChR deficiency (Engel and Sine 2005).
Clinical Sensitivity - Sequencing with CNV PGxome
Sensitivity for CMS testing is at least 50% overall; 30% for CHRNE, 10% for RAPSN, and 7.5% for COLQ (GeneReviews, Abicht and Lochmüller, 2006). CHRNA1 is a rare cause of CMS, and too few cases of LMPS have been reported to estimate sensitivity.
Testing Strategy
This test provides full coverage of all coding exons of the CHRNA1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).
Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).
Indications for Test
A comprehensive diagnostic algorithm can be found in (GeneReviews, Abicht and Lochmüller, 2006). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in CHRNA1.
A comprehensive diagnostic algorithm can be found in (GeneReviews, Abicht and Lochmüller, 2006). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in CHRNA1.
Gene
Official Gene Symbol | OMIM ID |
---|---|
CHRNA1 | 100690 |
Inheritance | Abbreviation |
---|---|
Autosomal Dominant | AD |
Autosomal Recessive | AR |
X-Linked | XL |
Mitochondrial | MT |
Diseases
Name | Inheritance | OMIM ID |
---|---|---|
Lethal Multiple Pterygium Syndrome | AR | 253290 |
Myasthenic Syndrome, Congenital, Fast-Channel | AR, AD | 608930 |
Myasthenic Syndrome, Congenital, Slow-Channel | AD | 601462 |
Citations
- Angela Abicht, Hanns Lochm?ller (2006). "Congenital Myasthenic Syndromes."
- Angela Abicht, Hanns Lochmuller (2006). "Congenital Myasthenic Syndromes."
- Byring RF, Pihko H, Tsujino A, Shen XM, Gustafsson B, Hackman P, Ohno K, Engel AG, Udd B. 2002. Congenital myasthenic syndrome associated with episodic apnea and sudden infant death. Neuromuscul Disord 12: 548-553. PubMed ID: 12117478
- Croxen R, Hatton C, Shelley C, Brydson M, Chauplannaz G, Oosterhuis H, Vincent A, Newsom-Davis J, Colquhoun D, Beeson D. 2002. Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology 59: 162-168. PubMed ID: 12141316
- Engel, A. G., et.al. (1996). "New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome." Hum Mol Genet 5(9): 1217-27. PubMed ID: 8872460
- Engel, A. G., Sine, S. M. (2005). "Current understanding of congenital myasthenic syndromes." Curr Opin Pharmacol 5(3): 308-21. PubMed ID: 15907919
- Michalk, A., et.al. (2008). "Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders." Am J Hum Genet 82(2): 464-76. PubMed ID: 18252226
- Ohno, K., et.al. (1996). "Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit." Neuron 17(1): 157-70. PubMed ID: 8755487
- Shen, X. M., et.al. (2006). "Slow-channel mutation in acetylcholine receptor alphaM4 domain and its efficient knockdown." Ann Neurol 60(1): 128-36. PubMed ID: 16685696
- Wang, H. L., et.al. (1999). "Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating." Nat Neurosci 2(3): 226-33. PubMed ID: 10195214
- Webster, R., et.al. (2004). "Mutation in the AChR ion channel gate underlies a fast channel congenital myasthenic syndrome." Neurology 62(7): 1090-6. PubMed ID: 15079006
Ordering/Specimens
Ordering Options
We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.
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.
- PGnome sequencing panels can be ordered via the myPrevent portal only at this time.
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.
For Requisition Forms, visit our Forms page
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
Specimen Requirements and Shipping Details
PGxome (Exome) Sequencing Panel
PGnome (Genome) Sequencing Panel
ORDER OPTIONS
View Ordering Instructions1) Select Test Type
2) Select Additional Test Options
No Additional Test Options are available for this test.