Congenital Myasthenic Syndromes Panel

Last modified: Mar 21, 2018


  • Is a 18 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of a congenital myasthenic syndrome.

Analysis methods

  • PLUS
  • SEQ


3-4 weeks

Number of genes


Test code


CPT codes

SEQ 81406
SEQ 81407
DEL/DUP 81479
SEQ 81479


The Blueprint Genetics Congenital Myasthenic Syndromes Panel (test code NE1701):

  • Is a 18 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) when ordering the Congenital Myasthenic Syndromes Panel

ICD-10 Disease
G70.2 Congenital myasthenic syndrome

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or post synaptic proteins. Abnormalities of proteins involved with neuromuscular transmission underlie CMS, limb girdle CMS, Pena-Shokeir syndrome, and multiple pterygium syndromes. These disorders may represent a phenotypic continuum of a single entity. Slow-channel CMS is caused by mutations in acetylcholine receptor subunits. Fatigable weakness affecting limb, ocular, facial, and bulbar muscles characterize CMS. Neonates present with feeding problems, choking, feeble cry, and facial, bulbar, and generalized skeletal muscle weakness. Patients presenting in later childhood typically have abnormal exercise-induced fatigue and difficulty running. Cardiac and smooth muscle are not involved. Cognitive skills, coordination, sensation, and tendon reflexes are normal. Most patients have symptoms prior to two years of age. Life threatening respiratory insufficiency may occur in affected neonates or older children.

Genes in the Congenital Myasthenic Syndromes Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
AGRN Myasthenic syndrome, congenital AR 10 10
CHAT Myasthenic syndrome, congenital AR 19 68
CHRNA1 Myasthenic syndrome, congenital AD/AR 24 34
CHRNB1 Myasthenic syndrome AD/AR 7 8
CHRND Myasthenic syndrome AD/AR 17 22
CHRNE Myasthenic syndrome AD/AR 34 126
CHRNG Multiple pterygium syndrome, Escobar syndrome AR 14 31
COLQ Myasthenic syndrome, congenital AR 16 66
DOK7 Myasthenic syndrome, congenital AR 18 70
DPAGT1 Congenital disorder of glycosylation, Myasthenic syndrome, congenital AR 15 30
FLAD1 Lipid storage myopathy due to FLAD1 deficiency (LSMFLAD) 9 10
GFPT1 Myasthenic syndrome, congenital AR 9 41
LAMB2 Nephrotic syndrome, Pierson syndrome AR 15 100
MUSK Myasthenic syndrome, congenital AR 13 17
PLEC Muscular dystrophy, limb-girdle, Epidermolysis bullosa AR 26 91
RAPSN Myasthenic syndrome, congenital AR 21 58
SCN4A Hyperkalemic periodic paralysis, Myotonia, potassium-aggravated, Paramyotonia congenita, Myasthenic syndrome, congenital, Normokalemic potassium-sensitive periodic paralysis AD/AR 57 110
STIM1 Stormorken syndrome, Immunodeficiency AD/AR 12 20

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
CHRNE Chr17:4806452 c.-94G>A NM_000080.3
CHRNE Chr17:4806453 c.-95G>A NM_000080.3
CHRNE Chr17:4806454 c.-96C>T NM_000080.3 rs748144899
CHRNE Chr17:4804936 c.501-16G>A NM_000080.3
RAPSN Chr11:47470715 c.-199C>G NM_005055.4
RAPSN Chr11:47470726 c.-210A>G NM_005055.4 rs786200905
RAPSN Chr11:47469717 c.193-15C>A NM_005055.4

Added and removed genes from the panel

Genes added Genes removed

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • 1479 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics congenital myasthenic syndromes panel covers classical genes associated with Congenital myasthenic syndrome, Congenital myasthenic syndrome, acetazolamide-responsive, Myasthenic syndrome, congenital, associated with episodic apnea, Myasthenic syndrome, congenital, associated with acetylcholine receptor deficiency, Congenital myasthenic syndrome, fast channel, Congenital myasthenic syndrome, slow channel, Myasthenic syndrome, congenital, with tubular aggregates 2, Familial limb-girdle myasthenic syndrome with tubular aggregates, myopathy, tubular aggregate, myasthenia, limb-girdle, familial and endplate acetylcholinesterase deficiency. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics' Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient's phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
The performance presented above reached by WES with the following coverage metrics
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%


The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.