Malignant Hyperthermia Panel, Sequencing

  • Use to determine genetic etiology of MH susceptibility (MHS) in individuals with known or suspected clinical history of MH.
  • Use to assess for MHS in healthy individuals with family history of MH.
  • Use to assess for a sequence variant previously identified in a family member.
  • A copy of the relative's genetic laboratory report documenting the familial variant is required.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle calcium regulation which is triggered by volatile anesthetics, either with or without the depolarizing muscle relaxant succinylcholine. Less commonly, manifestations may be precipitated by strenuous exercise or high environmental temperatures. Excessive calcium release from the sarcoplasmic reticulum leads to disturbance of the intracellular calcium ion homeostasis causing skeletal muscle contraction and hypermetabolism. The hypermetabolic state generates heat and excess lactate and can result in hypercarbia, tachycardia, hyperkalemia, hyperthermia, acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis, myoglobinuria, and potentially death. Episodes of MH require prompt diagnosis and treatment to reduce mortality. MH susceptibility may be assessed by functional laboratory testing (caffeine-halothane contracture test, otherwise known as in vitro contracture test) or molecular testing of MH-associated genes.

Disease Overview

Epidemiology/Prevalence

Approximately 1 in 2,000 individuals has a pathogenic variant in an MH susceptibility gene.  As not all MH susceptible individuals are exposed to triggering agents, the estimated prevalence of anesthesia-related MH is 1-2 per 100,000.

Typical Testing Strategy

  • Muscle biopsy and contracture testing is recommended for:
    • Individuals with suspected clinical history of MH
    • First-degree relatives of a proband with clinical history of MH, if proband cannot be tested or causative familial variant not known
    • At-risk family members when the MH-causing variant is not known
    • Individuals with suspected personal or known family history of MHS prior to military service
  • Molecular MHS testing is recommended for:
    • Individuals with confirmed/suspected clinical MH event or positive contracture test
    • Relatives of individuals with a positive contracture test or known MHS variant
      • When the causative pathogenic MHS variant is known in the family, molecular testing can be used to identify relatives at increased risk for MHS. If the causative pathogenic MHS variant in the family is not known or a relative tests negative for a known familial variant, contracture testing is used to assess susceptibility. 

Additional Guidance

Genetics

Genes

RYR1, CACNA1S

Etiology

Pathogenic germline gain-of-function variants in the RYR1 or CACNA1S genes

Penetrance

Incomplete

The overall penetrance is 40% for RYR1-associated MHS,  with a greater penetrance in males than in females. MH-susceptible individuals may have previous uneventful exposures to triggering anesthetics before developing an MH reaction. The probability of developing MH when exposed to triggers is 25% among all carriers of RYR1 pathogenic variants but 76% among individuals who have experienced a previous MH reaction. 

Inheritance

Autosomal dominant

Test Description

Clinical Sensitivity

Up to 60% for MHS 

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a diagnosis of MHS.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
    • Regulatory region and deep intronic variants
    • Large deletions/duplications in any of the tested genes
    • Noncoding transcripts
    • RYR1 (NM_000540) exon 91 is not sequenced due to technical limitations of the assay
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
Genes Tested
Gene MIM # Associated Disorders Inheritance

CACNA1S

114208

MHS 5

Hypokalemic periodic paralysis 1

AD

RYR1

180901

MHS 1

AD

Central core disease

AD/AR

Congenital neuromuscular disease with uniform type 1 fiber

AD/AR

King-Denborough syndrome

AD

Multiminicore myopathy

AR

AD, autosomal dominant; AR, autosomal recessive

References