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, 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|
RYR1: Deletion/duplication analysis is not offered for exons 48 or 49.