Congenital Myasthenic Syndrome Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10321 AGRN 81479,81479 Order Options and Pricing
ALG14 81479,81479
ALG2 81479,81479
CHAT 81479,81479
CHRNA1 81479,81479
CHRNB1 81479,81479
CHRND 81479,81479
CHRNE 81479,81479
CHRNG 81479,81479
COL13A1 81479,81479
COLQ 81479,81479
DOK7 81479,81479
DPAGT1 81479,81479
GFPT1 81479,81479
GMPPB 81479,81479
LAMA5 81479,81479
LAMB2 81407,81479
LRP4 81479,81479
MUSK 81479,81479
MYO9A 81479,81479
PLEC 81479,81479
PREPL 81479,81479
RAPSN 81479,81479
SCN4A 81406,81479
SLC18A3 81479,81479
SLC25A1 81479,81479
SLC5A7 81479,81479
SNAP25 81479,81479
SYT2 81479,81479
UNC13A 81479,81479
VAMP1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10321Genes x (31)81479 81406, 81407, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or post synaptic proteins involved in neuromuscular junction structure, function, or repair (Engel. 2018. PubMed ID: 29892917; Shieh and Oh. 2018. PubMed ID: 29655455; Lorenzoni et al. 2018. PubMed ID: 29696584; Abicht et al. 2016. PubMed ID: 20301347). CMS are highly heterogenous both clinically and genetically and 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. The prevalence of CMS is predicted to be 9.2 per one million children under the age of 18 (Parr et al. 2014. PubMed ID: 24500997). CMS are characterized by fatigable weakness affecting limb, ocular, facial, and bulbar muscles. Neonates present with feeding problems, choking, feeble cry, and muscle weakness. More severe cases can also present with arthrogryposis multiplex congenita, respiratory insufficiency, sudden apnea, and cyanosis. 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 adult onset is increasingly recognized (Farmakidis et al. 2018. PubMed ID: 30032336; Croxen et al. 2002. PubMed ID: 12141316). Electrophysiologic data indicate a decremental response upon slow repetitive nerve stimulation or abnormal single-fiber EMG responses. Symptoms are extremely variable, and are in some case induced by febrile illness, infection, or excitement (Abicht et al. 2016. PubMed ID: 20301347). 

Medical treatment varies based on the CMS subtype. Genetic testing can aid in determining which therapeutic may work best. Some drugs are helpful for certain types of CMS, but can be detrimental to others (Farmakidis et al. 2018. PubMed ID: 30032336). Colinesterase inhibitors and 3,4-diaminopyridine can increase the amount of acetylcholine released at the synaptic cleft, whereas fluoxetine and quinidine are open-channel blockers of the acetylcholine receptor (Farmakidis et al. 2018. PubMed ID: 30032336). Genetic testing may also aide in establishing a differential diagnosis and may assist reproductive planning.

Genetics

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with CMS.

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 by the following genes: AGRN, ALG14, ALG2, CHAT, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PREPL, RAPSN, UNC13A, SLC18A3. CMS caused by CHRNA1, CHRNB1, CHRND, CHRNE, PLEC, SLC5A7, SCN4A, VAMP1 can exhibit both autosomal recessive and autosomal dominant inheritance. The SLC25A1, SNAP25, and SYT2 genes are involved in autosomal dominant CMS. Causative variants may include missense, nonsense, splicing, regulatory, or copy number alterations. De novo variants are not a common cause of disease for the genes in this panel, but could be possible for autosomal dominant CMS. The proportion of cases caused by a de novo pathogenic variant is unknown.

The products of the genes in this panel are involved in in transmission at the neuromuscular junction via the release of acetylcholine from synaptic vesicles, which depends on the concerted action of multiple proteins. CMS is classified into three different subtypes based on the location of the affected protein within the neuromuscular junction: presynaptic, synaptic basal lamina-associated, and postsynaptic. About 85% of CMS is classified as postsynaptic. The CHRNA1, CHRNB1, CHRND, and CHRNE genes encode the transmembrane subunits of the nicotinic acetylcholine receptor (AChR). Gain of function variants in these genes can result in slow channel syndrome due to prolonged opening of the channel. 

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants. See also recent reviews on CMS (Engel. 2018. PubMed ID: 29892917; Shieh and Oh. 2018. PubMed ID: 29655455; Lorenzoni et al. 2018. PubMed ID: 29696584; Abicht et al. 2016. PubMed ID: 20301347).

Clinical Sensitivity - Sequencing with CNV PGxome

Based on several studies of genetically confirmed CMS, 50% of patients have pathogenic CHRNE variants, 15-20% of patients have pathogenic RAPSN variants, 10-15% of patients have pathogenic COLQ variants, 10-15% of patients have pathogenic DOK7 variants, 4-5% of patients have pathogenic CHAT variants, and 2% of patients have pathogenic GFPT1 variants (Abicht et al. 2016. PubMed ID: 20301347). Other genetic causes of CMS are considered rare and likely account for less than 1% of cases. 

Clinical sensitivity for copy number variations among the CMS genes is expected to be low because few gross deletions or duplications have been documented. One exception may be the CHAT gene for which a recurrent gross deletion and duplication has been reported (Stankiewicz et al. 2012. PubMed ID: 21948486).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients with the tetrad of fatigable weakness most pronounced in ocular and other cranial muscles, pediatric onset, negative myasthenia gravis autoantibody testing, and supportive eletrophysiologic results are prime candidates for CMS genetic testing (Farmakidis et al. 2018. PubMed ID: 30032336; Abicht et al. 2016. PubMed ID: 20301347).

Diseases

Name Inheritance OMIM ID
Combined D-2- and L-2-HydroxyGlutaric Aciduria AR 615182
Congenital Disorder Of Glycosylation Type 1I AR 607906
Congenital Disorder Of Glycosylation Type 1J AR 608093
Congenital Myasthenic Syndrome - RAPSN AR 608931
Congenital Myasthenic Syndrome, Acetazolamide-Responsive AR 614198
Endplate Acetylcholinesterase Deficiency AR 603034
Epidermolysa Bullosa Simplex And Limb Girdle Muscular Dystrophy AR 226670
Epidermolysis bullosa simplex with nail dystrophy AR 616487
Epidermolysis Bullosa Simplex With Pyloric Atresia AR 612138
Epidermolysis Bullosa Simplex, Ogna Type AD 131950
Escobar Syndrome AR 265000
Familial Infantile Myasthenia AR 254210
Familial Limb-Girdle Myasthenic Syndrome With Tubular Aggregates AR 610542
Fetal Akinesia Deformation Sequence AR 208150
Fetal akinesia deformation sequence 2 AR 618388
Fetal akinesia deformation sequence 3 AR 618389
Hyperkalemic Periodic Paralysis; HYPP AD 170500
Hypokalemic Periodic Paralysis, Type 2 AD 613345
Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies 619031
Lethal Multiple Pterygium Syndrome AR 253290
Muscular Dystrophy, Limb-Girdle, Type 2Q AR 613723
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 AR 615350
Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 AR 615351
Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 AR 615352
Myasthenia, Limb-Girdle, Familial AR 254300
Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency AR 616326
Myasthenic syndrome, congenital, 14, with tubular aggregates AR 616228
Myasthenic Syndrome, Congenital, 15, without Tubular Aggregates AR 616227
Myasthenic Syndrome, Congenital, 17 AR 616304
Myasthenic Syndrome, Congenital, 18 AD 616330
Myasthenic Syndrome, Congenital, 19 AR 616720
Myasthenic syndrome, congenital, 20, presynaptic AR 617143
Myasthenic syndrome, congenital, 21, presynaptic AR 617239
Myasthenic syndrome, congenital, 22 AR 616224
Myasthenic syndrome, congenital, 23, presynaptic AR 618197
Myasthenic syndrome, congenital, 24, presynaptic AR 618198
Myasthenic syndrome, congenital, 25 AR 618323
Myasthenic Syndrome, Congenital, 2A, Slow-Channel AD 616313
Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency AR 616314
Myasthenic syndrome, congenital, 3A, slow-channel AD 616321
Myasthenic syndrome, congenital, 3B, fast-channel AR 616322
Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency AR 616323
Myasthenic syndrome, congenital, 4A, slow-channel AR 605809
Myasthenic syndrome, congenital, 4B, fast-channel AR 616324
Myasthenic Syndrome, Congenital, 7, Presynaptic AD 616040
Myasthenic Syndrome, Congenital, 8, with Pre- and Postsynaptic Defects AR 615120
Myasthenic Syndrome, Congenital, 9, Associated with Acetylcholine Receptor Deficiency AR 616325
Myasthenic Syndrome, Congenital, Associated With Acetylcholine Receptor Deficiency AR 608931
Myasthenic Syndrome, Congenital, Fast-Channel AR 608930
Myasthenic Syndrome, Congenital, Slow-Channel AD 601462
Myasthenic syndrome, congenital, with tubular aggregates 2 AR 614750
Nephrotic Syndrome, Type 5, With Or Without Ocular Abnormalities 614199
Neuronopathy, Distal Hereditary Motor, Type VIIA AD 158580
Paramyotonia Congenita Of Von Eulenburg AD 168300
Pierson Syndrome AR 609049
Potassium Aggravated Myotonia AD 608390
Sclerosteosis 2 AR 614305
Spastic ataxia 1, autosomal dominant AD 108600
Syndactyly Cenani Lenz Type AR 212780

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