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  • Test code: 03281
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
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Invitae Congenital Myasthenic Syndrome Panel

Test description

The Invitae Congenital Myasthenic Syndrome Panel analyzes up to 21 genes that are associated with congenital myasthenic syndrome (CMS), a heterogeneous group of neuromuscular disorders characterized by fatigable weakness of the skeletal muscles and variable presentation of numerous other features. These genes were curated based on current available evidence to provide a comprehensive test for the genetic causes of CMS.

Given that congenital myasthenic syndromes are a heterogeneous group of disorders, identification of the underlying genetic cause can be useful in confirming a diagnosis of CMS, ruling out other disorders with similar clinical features, informing recurrence risk, and guiding treatment decisions.

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Primary panel (13 genes)

AGRN ALG2 CHAT CHRNA1 CHRNB1 CHRND CHRNE COLQ DOK7 DPAGT1 GFPT1 MUSK RAPSN

Add-on Preliminary-evidence Genes for Congenital Myasthenic Syndrome (8 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

ALG14 GMPPB LAMB2 LRP4 PLEC PREPL SCN4A SNAP25

Alternative tests to consider

In some cases, congenital myasthenic syndromes may have overlapping features with limb-girdle muscular dystrophies. If a limb-girdle muscular dystrophy is suspected, clinicians may consider the Invitae Limb-Girdle Muscular Dystrophy Panel or the Invitae Congenital Muscular Dystrophy panel. If a broader panel is desired, clinicians may consider the Invitae Comprehensive Neuromuscular Disorders panel, which includes genes associated with muscular dystrophies, myopathies, and CMS.

Congenital myasthenic syndromes are a heterogeneous group of inherited neuromuscular junction (NMJ) disorders that typically manifest between the neonatal period and early childhood. The most common presentation consists of fatigable weakness of the skeletal muscles, respiratory issues including apnea and choking spells, feeding difficulty, and eyelid ptosis. Other features, such as congenital arthrogryposis multiplex and respiratory insufficiency, may also occur (PMID: 25159927). Milder subtypes of CMS may present in adolescence or even adulthood, though the majority of individuals with CMS share similar age of onset and presentation. Biallelic mutations in the CHRNA1, CHRND, DOK7, MUSK, and RAPSN genes are also associated with fetal akinesia deformation sequence (FADS), a severe prenatal disorder characterized byfetal hypomobility, severe joint contractures, growth retardation, lung hypoplasia, and other malformations (PMID: 21984750, 18252226).

CMS diagnosis typically depends on a combination of factors, including clinical presentation, family history, genetic etiology, negative anti-ACh and anti-MuSK serum studies, and decremental electromyographic findings (PMID: 23622369).

Congenital myasthenic syndromes can be divided into subtypes based on the location (pre-, post-, or synaptic) and function of the proteins involved (acetylcholine receptors (i.e., slow- and fast-channel CMS), NMJ endplate proteins, glycosylation proteins). Overall, postsynaptic CMS is the most common subtype and accounts for approximately 85% of identified individuals with CMS. Of the remaining 15% of CMS cases, 10% are synaptic and 5% are presynaptic (PMID: 23622369).

GeneInheritanceAssociated subtypes of congenital myasthenic syndrome and other associated disorders
Autosomal dominantAutosomal recessiveX-linked
AGRN CMS8 with pre- and postsynaptic defects
ALG2 CMS14 with tubular aggregates, congenital disorder of glycosylation type Ii (CDG-Ii)
ALG14* CMS15 without tubular aggregates
CHAT presynaptic CMS6
CHRNA1 slow-channel CMS1A, fast-channel CMS1B, fetal akinesia deformation sequence
CHRNB1 slow-channel CMS2A, CMS2C with acetylcholine receptor deficiency
CHRND slow-channel CMS3A, fast-channel CMS3B, CMS3C with acetylcholine receptor deficiency, fetal akinesia deformation sequence
CHRNE slow-channel CMS4A, fast-channel CMS4B, CMS4C with acetylcholine receptor deficiency
COLQ CMS5 with endplate acetylcholinesterase deficiency
DOK7 limb-girdle CMS10, fetal akinesia deformation sequence
DPAGT1 CMS13 with tubular aggregates, congenital disorder of glycosylation type Ij (CDG-Ij)
GFPT1 CMS12 with tubular aggregates
GMPPB* dystrophy-dystroglycanopathy types A14, B14, and C14, CMS
LAMB2* nephrotic syndrome, type 5, with or without ocular abnormalities
LRP4* CMS17
MUSK CMS9 with acetylcholine receptor deficiency, fetal akinesia deformation sequence
PLEC* epidermolysis bullosa simplex (EBS), limb-girdle muscular dystrophy type 2Q (LGMD2Q), EBS with CMS
PREPL* CMS
RAPSN CMS11 with acetylcholine receptor deficiency, fetal akinesia deformation sequence
SCN4A* CMS16, hyper- and hypokalemic periodic paralysis, paramyotonia congenita
SNAP25* CMS18 with intellectual disability and ataxia

*Preliminary-evidence gene

According to recent studies, of all genetically identified individuals with congenital myasthenic syndrome, an estimated 50% have pathogenic variants in CHRNE, 15%–20% have pathogenic variants in RAPSN, and pathogenic variants in DOK7 and COLQ are each reported to account for approximately 10%–15%. Pathogenic variants in CHAT and GFPT1 have been identified in no more than 5% of individuals each (PMID: 15951177, 15907919, 21822932, 23468559). The Invitae Congenital Myasthenic Syndrome Panel also includes other genes that have been identified as rare causes of CMS, though the exact contribution of these genes to the overall detection rate is not yet known.

CMS caused by variants in the AGRN, ALG2, ALG14, CHAT, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMB2, LRP4, MUSK, PREPL and RAPSN genes is associated with autosomal recessive inheritance. The CHRNA1, CHRNB1, CHRND, CHRNE, PLEC, and SCN4A genes are associated with both autosomal recessive and dominant forms of CMS and/or FADS. The SNAP25 gene is associated with an autosomal dominant form of CMS.

Incomplete penetrance has been reported for some autosomal dominant forms of CMS, including slow-channel congenital myasthenic syndrome. Some forms of CMS are rare, and their penetrance is not known; however, the majority of CMS subtypes are thought to have penetrance that approaches 100% by adulthood.

Congenital myasthenic syndromes are rare disorders. The prevalence of genetically confirmed CMS is estimated at 9.2 cases per 1 million children under 18 years of age (PMID: 24500997), though that number is expected to increase in the future as more clinically diagnosed individuals undergo genetic testing.

The clinical spectrum of congenital myasthenic syndrome is variable. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression, inform recurrence risk, and guide treatment management, which is often dependent on subtype (PMID: 20301347).

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AGRN NM_198576.3
ALG14 NM_144988.3
ALG2 NM_033087.3
CHAT NM_020549.4
CHRNA1 NM_000079.3
CHRNB1 NM_000747.2
CHRND NM_000751.2
CHRNE* NM_000080.3
COLQ NM_005677.3
DOK7* NM_173660.4
DPAGT1 NM_001382.3
GFPT1 NM_002056.3; NM_001244710.1
GMPPB NM_021971.2; NM_013334.3
LAMB2 NM_002292.3
LRP4 NM_002334.3
MUSK NM_005592.3
PLEC NM_000445.4; NM_201378.3; NM_201384.2
PREPL* NM_006036.4
RAPSN* NM_005055.4
SCN4A NM_000334.4
SNAP25 NM_130811.2; NM_003081.3

CHRNE: Analysis includes the intronic variants NM_000080.3:c.-96C>T, NM_000080.3:c.-95G>A, and NM_000080.3:c.-94G>A.
DOK7: Analysis includes the intronic variant NM_001301071.1:c.54+14_+28delGGGGGGGGGGGGCGC.
PREPL: Only deletion/duplication analysis is offered for this gene.
RAPSN: Analysis includes the promoter variants NM_005055.3:c.-210A>G and NM_005055.3:c.-199C>G.