A person who is perfectly well until they are given one particular kind of anaesthetic, and then is not. It is the clearest case in medicine of a genotype that changes a decision — and the decision is simply to use a different drug.
Muscle contracts when calcium is released inside the cell, and relaxes when it is pumped back. The channel that releases it is called the ryanodine receptor, and in skeletal muscle it is built from the RYR1 gene.
Some variants in that gene make the channel too easy to open. Nothing happens in ordinary life — the trigger has to be unusual, and there is one: certain anaesthetic gases, and the muscle relaxant succinylcholine.
Under those drugs the channel opens and does not close properly. Calcium floods the muscle cell, the muscle contracts and cannot stop, and the energy that takes is released as heat. Body temperature climbs, muscle breaks down, potassium and acid pour into the blood.
It is a genuine emergency, and it is treatable — dantrolene closes the channel, and outcomes changed completely once it existed. But the far better answer is not to trigger it at all, which is entirely possible when somebody knows in advance.
The triggering agents are the volatile anaesthetics — desflurane, enflurane, halothane, isoflurane, methoxyflurane and sevoflurane — and succinylcholine.
What matters as much is what is not on that list. Local and regional anaesthesia, nitrous oxide, intravenous anaesthetics such as propofol, and the non-depolarising muscle relaxants are all safe. An anaesthetist who knows can give a general anaesthetic without any of the triggers. This is why the information is worth having, and why it is not a reason to avoid surgery.
Hundreds of RYR1 variants have been described, and only some of them are established as causing susceptibility. A second gene, CACNA1S, accounts for a smaller share. A consumer array carries almost none of this.
So a genotype that shows susceptibility is worth acting on, and a genotype that shows nothing is not evidence of safety. The diagnostic test is a contracture test on a muscle biopsy at a specialist centre, and it exists precisely because genetics does not settle the question.
The strongest clue is not genetic at all: an unexplained anaesthetic death or crisis in a blood relative.
If susceptibility runs in your family, or a genotype has raised it, the step that matters is telling an anaesthetist before an operation rather than during one. That is the whole intervention. It costs nothing, it works, and it is the reason this page exists.
Source. Gonsalves et al., CPIC Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of CACNA1S or RYR1 Genotypes (Clin Pharmacol Ther 2019, PMID 30499100).
Genetics. Autosomal dominant with incomplete penetrance. RYR1 accounts for the majority of malignant hyperthermia susceptibility; CACNA1S, encoding the alpha-1 subunit of the dihydropyridine receptor that couples excitation to RYR1, accounts for a smaller proportion. Only a subset of the several hundred described RYR1 variants is classified as diagnostic for susceptibility.
Position listed here. rs118192172 (RYR1 c.1840C>T, p.Arg614Cys) is among the best-characterised susceptibility variants. It is not on most consumer arrays, and its absence from a genotype file carries no information.
Triggering agents. Desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane and succinylcholine. Non-triggering alternatives include nitrous oxide, intravenous agents including propofol, non-depolarising neuromuscular blockers, and local or regional techniques.
Diagnosis. The caffeine-halothane contracture test (in vitro contracture test in Europe) on fresh muscle biopsy remains the diagnostic standard. A genotype classified as susceptible is actionable without contracture testing; a non-informative genotype does not exclude susceptibility.
Clinical use. Where susceptibility is known or suspected, a trigger-free anaesthetic is planned. Dantrolene is the specific treatment for an established crisis and must be immediately available wherever triggering agents are used.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Malignant Hyperthermia Susceptibility comes down to these specific, well-studied positions — not a diagnosis.
RYR1 · rs118192172
See detailed info →Research-derived gene–drug associations only — not a prescription, dosing guide, or medical advice. Always follow your prescriber's guidance.
| Gene | Drug | What the research shows |
|---|---|---|
| RYR1 | Volatile anaesthetics (desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane) | Avoid in a person with a susceptible genotype. These agents open the ryanodine receptor and are the classic trigger for a malignant hyperthermia crisis. A trigger-free anaesthetic is straightforward to plan when the anaesthetist knows in advance, which is the entire clinical value of this information. (CPIC Guideline for CACNA1S, RYR1 and Volatile Anesthetic Agents and Succinylcholine (Clin Pharmacol Ther 2019, PMID 30499100).) |
| RYR1 | Succinylcholine | Avoid in a person with a susceptible genotype. Succinylcholine triggers the same crisis and can also cause masseter spasm. Non-depolarising neuromuscular blockers are the alternative. (CPIC Guideline for CACNA1S, RYR1 and Volatile Anesthetic Agents and Succinylcholine (Clin Pharmacol Ther 2019, PMID 30499100).) |
| CACNA1S | Volatile anaesthetics and succinylcholine | CACNA1S encodes the voltage sensor that tells RYR1 to release calcium, and variants in it cause the same susceptibility through the same pathway. It accounts for a smaller share of cases than RYR1, and the prescribing consequence is identical: avoid the triggering agents. (CPIC Guideline for CACNA1S, RYR1 and Volatile Anesthetic Agents and Succinylcholine (Clin Pharmacol Ther 2019, PMID 30499100).) |
No. Penetrance is incomplete and a susceptible person can have uneventful anaesthetics before a crisis — it depends on the agents used and on factors that are not fully understood. An uneventful past is reassuring and it is not proof.
It tells you nothing either way. Hundreds of RYR1 variants have been described, only some are classified as causative, and consumer arrays carry almost none of them. The diagnostic test is a muscle contracture test, which exists because genotyping does not answer this.
No, and this is the part worth being clear about. Anaesthesia without any triggering agent is routine — regional techniques, nitrous oxide, propofol and non-depolarising relaxants are all safe. What is needed is that the anaesthetist knows beforehand.
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