Authors: Riazi S et al.
Anesthesiology 144(4):776–783, April 2026
Summary:
This article presents a practical, North American–focused framework for evaluating patients at risk for malignant hyperthermia (MH) in the era of widespread genetic testing. As genomic testing becomes more accessible and commonly performed—even as part of routine screening—anesthesiologists are increasingly encountering patients with genetic variants associated with MH without clear clinical history.
The authors emphasize that MH is a pharmacogenetic disorder primarily linked to mutations in the RYR1 gene, with smaller contributions from CACNA1S and STAC3. While genetic testing has become the first-line screening tool due to improved accessibility and reduced cost, it has limited sensitivity (up to ~70%), meaning a negative test does not fully exclude susceptibility. Historically, confirmatory testing with the caffeine-halothane contracture test (CHCT) has been the gold standard, but access is now extremely limited in North America, making genetic interpretation even more critical.
The core contribution of the article is a stepwise clinical decision algorithm that integrates three key elements: personal history, family history, and genetic test results. Rather than relying solely on genetic findings, the authors stress that results must be interpreted within clinical context. For example, patients with a personal or family history of MH or suggestive conditions (e.g., exertional rhabdomyolysis, hyperCKemia) should be managed as MH-susceptible regardless of genetic results.
A major challenge highlighted is the interpretation of variants of uncertain significance (VUS), which are increasingly common with expanded genetic panels. The authors recommend a conservative approach—particularly for higher-risk variants (VUS-Hi)—favoring treatment as MH-susceptible even though many of these patients will ultimately be false positives. This reflects a risk-averse strategy given the potentially fatal consequences of MH and the relative ease of avoiding triggering agents.
The article also addresses real-world clinical scenarios, including obstetric management and patients with incidental genetic findings. Importantly, it reframes MH risk assessment away from attempting precise risk prediction toward practical perioperative decision-making—primarily whether to use triggering or nontriggering anesthetics.
Ultimately, the authors advocate for a pragmatic, safety-focused approach that prioritizes prevention, simplifies decision-making, and reflects the realities of limited access to confirmatory testing in North America.
Key Points:
- Genetic testing is now first-line for MH risk assessment but has limited sensitivity
- RYR1 mutations account for the majority of MH susceptibility cases
- Interpretation of genetic results must be combined with clinical and family history
- Variants of uncertain significance create major clinical decision challenges
- A conservative “treat as MH-susceptible” approach is recommended in higher-risk scenarios
What You Should Know:
You’re going to see more of this—patients walking in with genetic results you didn’t order. The mistake is treating the test as the diagnosis. This paper makes it simple: combine history + genetics, and when in doubt, err on safety. Avoiding triggers is easy—missing MH is not.
We would like to thank Anesthesiology for allowing us to summarize and share this article.