Congenital Myasthenic Syndrome Panel

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.

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).

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).

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. 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).