Malignant Hyperthermia Susceptibility Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10059 CACNA1S 81479,81479 Order Options and Pricing
RYR1 81408,81479
STAC3 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10059Genes x (3)81479 81408, 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.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

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

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Malignant Hyperthermia (MH) is a severe adverse reaction to commonly used anesthetics (halothane, sevoflurane, desflurane, enflurane, isoflurane) or to depolarizing muscle relaxants (succinylcholine) (Nelson and Flewellen 1983; Larach et al. 2010; Rosenberg et al. 2013). In susceptible patients these agents may trigger uncontrolled muscle hypermetabolism. In almost all cases, the first manifestations of MH occur in the operating room. Death can result unless the patient is promptly treated. Alternative anesthetics are available for known MH Susceptible individuals.

Genetics

Malignant Hyperthermia (MH) Susceptibility may be caused by mutations in at least three genes: RYR1, CACNA1S and STAC3. Causative mutations in RYR1 are much more common than causative mutations in the other two genes.

RYR1 mutations causative for MH are inherited in an autosomal dominant manner, although patients with two causative mutations in trans have been reported (Monnier et al. 2002). All RYR1 MH causative mutations reported in the literature have been either missense or (rarely) in-frame deletion or insertion of one or a few amino acids (Robinson et al. 2006; Ibarra et al. 2006; Levano et al. 2009; www.emhg.org). Premature protein termination, splicing, or large deletion mutations have not been reported in RYR1 for MH (although they are well known in cases of recessive myopathy). Over 300 RYR1 missense variants have been found in MH patients, but only 35-50 have been conclusively demonstrated to be involved in the disease. Most causative RYR1 MH mutations are clustered in three hot spots along the gene. Penetrance of many (and perhaps all) RYR1 MH causative variants is incomplete; that is, MH susceptible patients will not always trigger upon exposure to offending agents (Robinson et al. 2009; Grievink and Stowell 2010). The large RYR1 gene with 106 exons encodes the primary skeletal muscle calcium channel within the sarcoplasmic reticulum membrane. Mutations in RYR1 can also cause a variety of myopathies (see Test #1771).

Autosomal dominant MH may also be caused by mutations in the CACNA1S gene (Monnier et al. 1997; Carpenter et al. 2009; Toppin et al. 2010). Several CACNA1S missense variants have been connected to MH, but to date the only variant conclusively demonstrated to be involved is c.3257G>A (p.Arg1086His). CACNA1S encodes the α1 subunit of the L-type calcium channel in skeletal muscle, also known as the dihydropyridine receptor. The CACNA1S and RYR1 gene products interact to transduce action potentials into contraction of skeletal muscle fibers (Lanner et al. 2010). Missense mutations in the CACNA1S gene can also cause hypokalemic periodic paralysis.

Recently, a founder missense mutation in the STAC3 gene has been reported to cause autosomal recessive Native American myopathy (Horstick et al. 2013). This myopathy is characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities and susceptibility to MH (Stamm et al. 2008). STAC3 encodes a T-tubule protein which mediates Ca++ release through the RYR1 channel (Nelson et al. 2013). The involvement of STAC3 in MH is not as well established as the other two genes, but we included this gene in our NGS panel to be inclusive.

Testing Strategy

This panel provides 100% 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).

Clinical Sensitivity - Sequencing with CNV PGxome

Sensitivity for ideal test candidates (family history of MH plus either positive in vitro contracture test or an MH event) is approximately 60% (Monnier et al. 2005; Levano et al. 2009).

No large deletions or insertions in any of the three genes have been reported in MH patients.

Indications for Test

Ideal MH test candidates have a family history of MH along with either a positive in vitro contracture test or a clear MH event. Testing should begin in such a family member. If a causative mutation is identified, other family members can be screened at much reduced cost. Other, less ideal candidates for testing are those with just a family history of MH or those with a “MH-like” event and no family history.

Genes

Official Gene Symbol OMIM ID
CACNA1S 114208
RYR1 180901
STAC3 615521
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Carpenter D, Ringrose C, Leo V, Morris A, Robinson RL, Halsall PJ, Hopkins PM, Shaw M-A. 2009. The role of CACNA1S in predisposition to malignant hyperthermia. BMC Med Genet 10: 104. PubMed ID: 19825159
  • Grievink H, Stowell KM. 2010. Research Allele-specific differences in ryanodine receptor 1 mRNA expression levels may contribute to phenotypic variability in malignant hyperthermia. Orphanet J Rare Dis 5: 10. PubMed ID: 20482855
  • Horstick EJ, Linsley JW, Dowling JJ, Hauser MA, McDonald KK, Ashley-Koch A, Saint-Amant L, Satish A, Cui WW, Zhou W, Sprague SM, Stamm DS, Powell CM, Speer MC, Franzini-Armstrong C, Hirata H, Kuwada JY. 2013. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun 4: 1952. PubMed ID: 23736855
  • Ibarra M CA, Wu S, Murayama K, Minami N, Ichihara Y, Kikuchi H, Noguchi S, Hayashi YK, Ochiai R, Nishino I. 2006. Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. Anesthesiology 104: 1146–1154. PubMed ID: 16732084
  • Lanner JT, Georgiou DK, Joshi AD, Hamilton SL. 2010. Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release. Cold Spring Harbor Perspectives in Biology 2: a003996–a003996. PubMed ID: 20961976
  • Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. 2010. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth. Analg. 110: 498-507. PubMed ID: 20081135
  • Levano S, Vukcevic M, Singer M, Matter A, Treves S, Urwyler A, Girard T. 2009. Increasing the number of diagnostic mutations in malignant hyperthermia. Human Mutation 30: 590–598. PubMed ID: 19191329
  • Monnier N, Kozak-Ribbens G, Krivosic-Horber R, Nivoche Y, Qi D, Kraev N, Loke J, Sharma P, Tegazzin V, Figarella-Branger D, Roméro N, Mezin P, et al. 2005. Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. Human Mutation 26: 413–425. PubMed ID: 16163667
  • Monnier N, Krivosic-Horber R, Payen J-F, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J. 2002. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 97: 1067–1074. PubMed ID: 12411788
  • Monnier N, Procaccio V, Stieglitz P, Lunardi J. 1997. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am. J. Hum. Genet. 60: 1316–1325. PubMed ID: 9199552
  • Nelson BR, Wu F, Liu Y, Anderson DM, McAnally J, Lin W, Cannon SC, Bassel-Duby R, Olson EN. 2013. Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility. Proc. Natl. Acad. Sci. U.S.A. 110: 11881–11886. PubMed ID: 23818578
  • Nelson TE, Flewellen EH. 1983. Current concepts. The malignant hyperthermia syndrome. N. Engl. J. Med. 309:416-418. PubMed ID: 6348539
  • Robinson R, Carpenter D, Shaw M-A, Halsall J, Hopkins P. 2006. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum. Mutat. 27: 977–989. PubMed ID: 16917943
  • Robinson RL, Carpenter D, Halsall PJ, Iles DE, Booms P, Steele D, Hopkins PM, Shaw M-A. 2009. Epigenetic allele silencing and variable penetrance of malignant hyperthermia susceptibility. British Journal of Anaesthesia 103: 220–225. PubMed ID: 19454545
  • Rosenberg H, Sambuughin N, Riazi S, Dirksen R. 2013. Malignant Hyperthermia Susceptibility. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301325
  • Stamm DS, Aylsworth AS, Stajich JM, Kahler SG, Thorne LB, Speer MC, Powell CM. 2008. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. Am. J. Med. Genet. A 146A: 1832–1841. PubMed ID: 18553514
  • Toppin PJ, Chandy TT, Ghanekar A, Kraeva N, Beattie WS, Riazi S. 2010. A report of fulminant malignant hyperthermia in a patient with a novel mutation of the CACNA1S gene. Canadian Journal of Anesthesia/Journal canadien d’anesthésie 57: 689–693. PubMed ID: 20431982

Ordering/Specimens

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