The Invitae Malignant Hyperthermia Susceptibility Panel analyzes two genes that are associated with malignant hyperthermia susceptibility (MHS), a pharmacogenetic disorder of skeletal muscle that is caused by pathogenic variants in the RYR1 and CACNA1S genes. MHS is associated with a hypermetabolic response after exposure to certain environmental factors, such as inhaled volatile anesthetic agents.
The clinical presentation of MHS may be variable and overlaps with other disorders. Identification of the underlying genetic cause may direct medical treatment and inform recurrence risk.
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of calcium regulation in skeletal muscle that can lead to a hypermetabolic response upon exposure to certain environmental factors, including inhaled volatile anesthetics and the muscle relaxant succinylcholine. Symptoms of MHS can include tachycardia, muscle rigidity, an increase in end-expired carbon dioxide concentration, tachypnea, hypercapnia, rhabdomyolysis, and death. The clinical manifestations can vary depending on the triggering agent and other factors, such as metabolic state and body temperature; these manifestations can be life-threatening if they are not treated. Individuals with MHS may not experience an episode every time they are exposed to a triggering agent. Rarely does malignant hyperthermia occur in a non-anesthetized patient.
A diagnosis of MHS can be confirmed with a positive caffeine-halothane contracture test (CHCT) result on muscle tissue or upon identification of a RYR1 or CACNA1S pathogenic variant.
RYR1 is the most common gene associated with MHS, accounting for 70%–80% of affected individuals. CACNA1S is a rare cause of MHS and accounts for an estimated 1% of affected individuals.
MHS is inherited in an autosomal dominant manner.
An estimated 50% of individuals who have MHS and are exposed to a triggering anesthetic agent do not experience an adverse reaction.
The prevalence of MHS is difficult to determine because many individuals who carry a pathogenic variant may remain asymptomatic, even if exposed to a triggering agent. Estimates of prevalence vary from 1 in 400 to 1 in 10,000.
Genetic testing for MHS may be useful in patients or their relatives who have MHS or a history of a suspected MH episode. Testing may also be useful for individuals with a positive caffeine-halothane contracture test (CHCT) result. Genetic testing may be a less-invasive option than CHCT testing, which requires a muscle biopsy, although a negative genetic test result does not rule out a diagnosis of MHS. The clinical presentation of MHS can be variable, and genetic testing may confirm a suspected diagnosis or rule out other disorders with similar presentations. A genetic diagnosis may also impact medical management, including anesthetic usage, and may help inform recurrence risk.
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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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|