New Study Finds Lamotrigine PGx Panels Are Testing the Wrong HLA Gene

ScreenMyGene Team·Published September 3, 2026·8 min read·Clinically reviewed by Dr. Ashraf, Ph.D.

Laboratory scientist reviewing HLA genotyping and DNA data visualizations on a laptop in a modern genomics lab

Short answer: A September 2026 JAMA Network Open study found that the HLA markers on most pharmacogenomic panels ordered before lamotrigine — HLA-B*15:02 and HLA-A*31:01 — were validated for carbamazepine, not lamotrigine, and showed no association with lamotrigine-induced DRESS. The actual marker, HLA-A*32:01, appeared in 41.4% of DRESS cases versus 4.1% of controls. It is not on most panels ordered today.

What the new study found

Researchers at Vanderbilt University Medical Center, working with Mass General Brigham, Mayo Clinic, the University of Florida, and Murdoch University, ran a matched case-control study comparing 29 patients with lamotrigine-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) — enrolled between 2016 and 2025 — against 290 lamotrigine-tolerant controls drawn from Vanderbilt's BioVU biobank. The results, published September 2, 2026 in JAMA Network Open, identified HLA-A*32:01 as the allele associated with lamotrigine-induced DRESS: present in 41.4% of cases versus 4.1% of controls, a 16.4-fold increase in odds. The two alleles most commonly tested before lamotrigine today, HLA-B*15:02 and HLA-A*31:01, showed no significant association with the reaction in U.S. populations in this cohort.

Senior author Elizabeth Phillips, MD, director of Vanderbilt's Center for Drug Safety and Immunology, put the practical problem plainly: the test being ordered "was built for a different drug," and for lamotrigine "a negative result can be misinterpreted as a green light."

Why panels are testing the wrong gene

The mix-up traces to drug-class logic, not lab error. HLA-B*15:02 is a well-established, CPIC-guideline-backed marker for carbamazepine- and oxcarbazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis, concentrated in patients of Southeast Asian ancestry. HLA-A*31:01 has a broader, weaker association with carbamazepine hypersensitivity across ancestries. Because lamotrigine is chemically distinct from carbamazepine but is grouped with it clinically as an antiepileptic and mood stabilizer with DRESS/SJS-TEN risk on its FDA label, many pharmacogenomic panels and clinical pathways carried the carbamazepine markers over to lamotrigine by association rather than by drug-specific evidence. There is currently no CPIC guideline for lamotrigine-specific HLA testing, which left a coverage gap that this study is the first to fill with a validated allele.

That gap matters because DRESS from lamotrigine is not a hypothetical: with an incidence estimated between 1 in 1,000 and 1 in 10,000 exposed patients and a reported mortality of 3% to 10%, it is one of the more dangerous idiosyncratic drug reactions in psychiatry and neurology practice, and lamotrigine ranks among the top five drug causes of DRESS worldwide.

Carriers of HLA-A*32:01 were about 10 times more common among lamotrigine-DRESS cases than among tolerant controls — a 16.4-fold difference in odds.

What this means for panel design, ordering, and billing

For clinical laboratories, medical directors, and the RCM teams that support them, this study has three immediate implications, independent of what any future CPIC guideline eventually says:

Panel content: A pharmacogenomic panel that reports HLA-B*15:02 and/or HLA-A*31:01 as "lamotrigine risk" markers is reporting an unvalidated association. Labs building or licensing PGx panels should review how lamotrigine is represented in patient- and clinician-facing reports and whether the marketing or report language implies coverage the evidence does not support.
Medical necessity documentation: Because HLA-A*32:01 typing is not yet named in a payer LCD or CPIC guideline specific to lamotrigine, medical necessity language for ordering it will need to rest on the peer-reviewed evidence itself (this study) plus drug-label DRESS/SJS-TEN risk language, not on an existing PGx coverage policy. Expect payers to be slow to add explicit coverage until a professional guideline catches up.
Coding: HLA-A*32:01 is a Class I, single-allele, high-resolution HLA typing target — the same code family already used to bill HLA-B*15:02 typing (the 8138x HLA typing range). It is not a new procedure requiring a new code; it is an existing code applied to a different, better-validated target. That makes it operationally easy for labs already running HLA-B*15:02 assays to add HLA-A*32:01 without new CLIA validation infrastructure, using the rapid PCR methodology the study authors note is already available and inexpensive.

The scale question: is testing worth it?

Lamotrigine was prescribed to an estimated 2.5 million Americans in 2024. At a DRESS incidence of roughly 1 in 1,000 to 1 in 10,000 and an HLA-A*32:01 carrier rate of 41.4% among cases, the study authors calculate that approximately 2,400 patients would need to be screened to prevent one case of DRESS. Reviewers covering the study note that because HLA-A*32:01 was present in fewer than half of DRESS cases (41.4%), a negative result narrows risk but does not eliminate it — this is a risk-stratification marker, not a rule-out test, which has implications for how any future clinical decision support language should be worded to ordering clinicians.

The alleles validated for carbamazepine-class drugs are not the allele this study associates with lamotrigine DRESS risk.

Scale of the exposure versus the scale of the intervention: a large prescribed population, a modest number-needed-to-screen, and a reaction that is rare but frequently severe.

What labs and clinical teams should do now

This is a single case-control study, not yet a CPIC guideline or an FDA label change, and its authors are explicit that HLA-A*32:01 negativity does not rule out DRESS risk. That argues for a measured response rather than an overnight panel overhaul:

Audit existing PGx panels and clinical decision support content for any lamotrigine-specific claims tied to HLA-B*15:02 or HLA-A*31:01, and correct language that implies a validated, drug-specific association.
Track whether CPIC, the FDA label, or a payer LCD updates in response to this publication — none currently name HLA-A*32:01 for lamotrigine, so coverage and medical-necessity criteria will lag the science.
For labs evaluating whether to add HLA-A*32:01 to existing HLA typing menus, weigh the existing CLIA-validated PCR infrastructure most HLA labs already run against the ~2,400-needed-to-test economics the study reports, and loop in the ordering psychiatry/neurology base before assuming self-pay or payer reimbursement.
Flag lamotrigine specifically in any prior-authorization or medical necessity documentation workflow — the marker gap is a documentation and decision-support risk today, independent of whether a formal coverage policy exists yet.

Frequently asked questions

Does this mean current lamotrigine pharmacogenomic testing is useless?

Not useless, but misapplied. HLA-B*15:02 and HLA-A*31:01 remain clinically valid for carbamazepine and oxcarbazepine. The study found no evidence they predict lamotrigine-induced DRESS, so a negative result on those alleles should not be read as reassurance specifically for lamotrigine risk.

Is HLA-A*32:01 testing available today?

Yes. The study authors note that rapid PCR assays for HLA-A*32:01 already exist and are inexpensive, and it is already used clinically to detect vancomycin-induced DRESS risk, so the assay methodology is established even though its use for lamotrigine is new.

Will CPIC or the FDA update guidance because of this study?

Unknown as of this writing. This is one case-control study; professional guideline bodies typically wait for replication or a larger cohort before issuing formal dosing or testing guidance. Labs should not represent HLA-A*32:01 as CPIC- or FDA-mandated for lamotrigine until that happens.

What CPT code would cover HLA-A*32:01 typing?

It falls under the existing Class I, high-resolution, single-allele HLA typing code range already used for HLA-B*15:02 testing — not a new code. Payer coverage and medical necessity criteria specific to lamotrigine, however, do not yet exist and will need to be built from the primary literature.

How rare is lamotrigine-induced DRESS in practice?

The study cites an incidence of roughly 1 in 1,000 to 1 in 10,000 exposed patients, with a reported mortality of 3% to 10%. Rare in absolute terms, but lamotrigine is prescribed to millions of Americans annually and ranks among the top five drug causes of DRESS worldwide.

This article is educational and intended for laboratory, clinical, and revenue-cycle professionals evaluating pharmacogenomic test design and coverage strategy. It is not clinical, coding, or billing advice for any individual patient or claim, and it does not represent a CPIC, FDA, or payer policy position. Confirm current guideline status and payer coverage before changing panel content, ordering practices, or claims documentation. ScreenMyGene's pharmacogenomics decision-support module and guide to genetic testing denials cover how panel-level evidence gaps like this one translate into medical necessity and claims risk.

Sources: Krantz M, et al. "HLA-A*32:01 and Lamotrigine-Induced Drug Reaction With Eosinophilia and Systemic Symptoms," JAMA Network Open, Sept. 2, 2026 (Vanderbilt University Medical Center, Mass General Brigham, Mayo Clinic, University of Florida, Murdoch University) — reported via Vanderbilt University Medical Center news release, Clinical Lab Products, and HCPLive.