A newly identified genetic risk marker for a severe lamotrigine reaction is missing from commonly used testing panels.
A genetic marker already utilized to detect the risk of a severe adverse reaction to the antibiotic vancomycin also identifies patients at risk of developing the same reaction to lamotrigine, according to a study led by researchers at Vanderbilt University Medical Center and published in JAMA Network Open.
The researchers reported that the allele, HLA-A*32:01, is currently missing from the standard pharmacogenomic panels that clinicians order prior to prescribing lamotrigine. Furthermore, the two genetic variants that are routinely included on those pre-prescription panels demonstrated no association with adverse lamotrigine reactions in a US population.
Lamotrigine serves as a first-line treatment for seizure and bipolar disorders and was prescribed to an estimated 2.5 million people in the US in 2024. However, the medication ranks among the top five causes worldwide of drug reaction with eosinophilia and systemic symptoms (DRESS), a condition that carries a 3% to 10% mortality rate and can lead to severe organ damage and long-term complications. DRESS affects an estimated 1 in 1,000 to 1 in 10,000 patients who take the drug.
Mismatch in Routine Pharmacogenomic Testing
Neurologists and psychiatrists frequently order pharmacogenomic panels before initiating aromatic antiseizure medications. Currently, those panels test for HLA-B15:02 and HLA-A31:01, variants originally validated to assess risk for reactions to carbamazepine. Neither allele had been validated for lamotrigine in a US population.
“The test being ordered was built for a different drug, yet for lamotrigine a negative result can literally be misinterpreted as a green light, offering reassurance that the evidence simply does not support,” says Elizabeth Phillips, MD, professor of medicine in the Division of Infectious Diseases, director of the Center for Drug Safety and Immunology at Vanderbilt Health, and corresponding author of the study, in a release.
In the matched case-control study, investigators evaluated 29 patients with lamotrigine-induced DRESS enrolled prospectively between 2016 and 2025 at Vanderbilt Health and Mass General Brigham. They compared these cases with 290 lamotrigine-tolerant controls matched on age, sex, and self-reported race.
The study found that HLA-A32:01 was present in 41.4% (12 of 29) of patients who developed DRESS, compared to 4.1% (12 of 290) of the control group. This represents a 16.4-fold higher odds of developing the condition, marking the strongest genetic association reported for lamotrigine-induced DRESS to date. By contrast, HLA-A31:01 showed no statistically significant difference between groups, and HLA-B*15:02 was not detected in any study participants.
Clinical and Diagnostic Implications
The study authors noted that because a rapid polymerase chain reaction (PCR) assay for HLA-A*32:01 has already been developed for vancomycin-induced DRESS, the test is inexpensive and readily available for clinical laboratories to implement.
“That performance is in the same range as a test already in routine use for carbamazepine, so it’s not a hypothetical standard — it’s the one the field has accepted,” says Matthew Krantz, MD, assistant professor of medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt Health and first author of the study, in a release.
The authors also outlined key limitations of the findings, noting that because HLA-A*32:01 was present in fewer than half of the DRESS cases, the allele is neither necessary nor sufficient to cause the reaction, meaning a negative test does not entirely eliminate risk. Researchers estimate that approximately 2,400 patients would need to undergo testing to prevent a single case of DRESS. Additionally, because the study cohort was small and 79.3% white, the authors cautioned that the findings were powered primarily for large effect sizes and do not exclude other potential genetic associations in broader populations.
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