Mitochondrial m.11232T>C-linked Volatile Anesthetic Hypersensitivity: Anesthesia and Genetic Testing Recommendation Guidelines

A Knowledge Portal for a Safety Concern of Severe Anesthetics Hypersensitivity Associated with Indigenous American Ancestry Carrying Mitochondrial DNA Variant m.11232T>C (T11232C)

Introduction
This knowledge portal provides resources, society statements/guidelines, and factual information regarding severe anesthetic hypersensitivity associated with individuals of Indigenous American Ancestry, frequently carrying the mitochondrial DNA (mtDNA) variant m.11232T>C.

Background

Recent reports have identified a link between Indigenous American Ancestry and severe adverse outcomes or death following the administration of sevoflurane, a volatile anesthetic. These outcomes are hypothesized to be associated with the mitochondrial DNA (mtDNA) variant NC_012920:m.11232T>C in the MT-ND4 gene.

The variant appears to originate in populations with maternal lineages tracing to Carabobo, Venezuela, where m.11232T>C may represent a haplogroup-defining variant in previously underrecognized mtDNA lineage(s).

Affected individuals have typically been previously healthy children and adults undergoing brief anesthesia for routine, minor procedures. The reactions appear to be primarily associated with sevoflurane.

While there are no peer-reviewed publications as of February 7, 2026, we are aware of at least 10 cases in countries including Venezuela, Chile, Spain, and the US, and that several manuscripts are in preparation. This emerging issue has prompted statements from multiple national and international anesthesiology societies, including those in Venezuela, Chile, Spain, and the United States (American Society of Anesthesiologists and the Society for Pediatric Anesthesia).

Given the 30-year history of sevoflurane use, it is likely that these cases have been historically underrecognized.

This knowledge portal has been created to share resources and information about this emerging issue and to provide a place for people to share information as it becomes available. We will update this page as new information is published, and we welcome contributions from the community.

Statements and Guideline from Clinical Societies Worldwide

Anesthesia and Genetic Testing Recommendation Guidelines (Version 1, February 27, 2026 ( To be added).
   A Joint Communication of the American College of Medical Genetics (ACMG), American Society of Anesthesiologists (ASA), and Society for Pediatric Anesthesia (SPA)

American Society of Anesthesiologists (ASA) and the Society for Pediatric Anesthesia (SPA): Update regarding severe neurological complications and death after general anesthesia in adult and pediatric patients of Venezuelan ancestry (January 27, 2026)
 
Canadian Anesthesiologists’ Society Advisory Statement, Emerging Reports of Severe Neurologic Complications Following General Anesthesia in Patients with Maternal Venezuelan Ancestry (March, 2026)
 
Clinical considerations from Chilean Society of Anesthesiologists (February, 2026)
 
Spanish Society of Anesthesiology and Resuscitation (SEDAR) Medical Alert: Genetic mutation in children of Venezuelan origin and anesthetic complications (July 2025)   
 
Venezuelan Society of Anesthesiology (February 12, 2026)   

Scientific and Clinical Knowledge

Publications and Conference Presentations:
PubMed    Google Scholar   

Searche with keywords" ((Anesthetics[Title/Abstract]) AND (m.11232T>C[Title/Abstract])) AND (Mitochondrial[Title/Abstract]) in PubMed, Google Scholar, and conference abstracts.

The Variant m.11232T>C and Haplogroup D1

The mitochondrial DNA variant m.11232T>C is extremely rare in global populations, appearing only twice at low heteroplasmy in large public databases (gnomAD, HelixMT). This rarity may suggest its role in the ancetry-specific anesthetics hypersensitivity being investigated here.
Recent analyses indicate this variant may be a haplogroup-defining mutation for a previously underrecognized sub-lineage of haplogroup D1, specific to certain Indigenous American populations, particularly those with maternal ancestry tracing to Venezuela.
This specific D1 sub-lineage is not represented in the current PhyloTree v17 reference. The variant is typically found at or near homoplasmy in affected individuals.

Publications
  • March 10, 2026
    Sanz-Pons, J., Aladrén-Herrer,C., Ortigoza-Escobar, J. et al.
    Effects of a mitochondrial genetic variant on sevoflurane hypersensitivity.
    Anesthesiology ():10.1097/ALN.0000000000006029, March 09, 2026. | DOI: 10.1097/ALN.0000000000006029
    •       Accompanying Editorial:  Levy RJ, Morgan PG. Ancient mitochondrial genetic variant, modern-day Pandora’s box. Anesthesiology 2026 (Coming online soon)

  • February 18, 2026
    Yanez Hinojosa, Constanza I. M.D., M.M.Sc.1; Anríquez Jiménez, Samanta Dr.P.H., M.D., M.Sc.2; Lara Román, Cristian Felipe M.Sc.2; Fuentes Contreras, Javiera Esperanza M.D.2; Pacheco Jara, Jorge Felipe M.D., M.Sc.2.

    Potential Mitochondrial Pharmacogenetic Susceptibility to Severe Neurologic Events after General Anesthesia: Report from the Chilean Ministry of Health.
    Anesthesiology ():10.1097/ALN.0000000000005935, February 18, 2026. | DOI: 10.1097/ALN.0000000000005935

  • March 2, 2023
    Estephania Candelo, Akemi Arango, Daniela Franco et al.
    Fatal outcome in a patient with an unknown mitochondrial disease after anesthetic exposure. A clinical literatura review from the anesthetic perspective, 02 March 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-2539495/v1]

  • Sep 30, 2025
    Rozo L, Franco OH, Bonilla A.
    Mitochondrial Genetic Susceptibility to Anesthetic Neurotoxicity in Venezuelan Pediatric Patients: A Call for Vigilance and Further Research.
    Archives of Surgery and Clinical Research, 2025; 9(2): 042-044. Available from:https://dx.doi.org/10.29328/journal.ascr.1001091

    • Related Publications - Mitochondrial disease and anesthetic hypersensitivity
  • October 1, 2021
    Hsieh VC, Niezgoda J, Sedensky MM, Hoppel CL, Morgan PG.
    Anesthetic Hypersensitivity in a Case-Controlled Series of Patients With Mitochondrial Disease.
    Anesth Analg. 2021;133(4):924-932. doi:10.1213/ANE.0000000000005430

    • Social Media, Press Release, and Other Channels
  • March 11, 2026
    Debnath Chatterjee, MD, FAAP, Phil G. Morgan, MD, Randall M. Clark, MD, FASA, Richard J. Levy, MD, FAAP.
    Breaking news: New Evidence Alert: Mitochondrial-Linked Hypersensitivity to Volatile Anesthetics

    • Genetic Testing Providers and Data Analysis Resources

    1. US and Worldwide Clinical Diagnostic Testing Labs

    T11232C Genetic Testing Products Comparison

    Data are collected as of March 4, 2026

    Information Type

    Provider 1 (CHOP Division of Genomic Diagnostics - DGD)

    Provider 2 (GeneDx)

    Provider 3 (Baylor Genetics)

    Test Name

    1. Targeted mtDNA Analysis

    2. MitoGenome sequencing

    1.      Test 453: 1-3 Known mtDNA variants;

    2.      Test 554: Entire mtDNA sequencing

    1.      Mitochondrial Whole Genome Sequence Analysis (Familial Mutation/Variant Analysis) (Sanger)

     

    2.      Comprehensive mtDNA Analysis by Massively Parallel Sequencing (NGS):

    Test Code

    TMTSC

    MITSP

    453; 554

    3056 (Sanger)

    2055 (NGS)

    CPT Code

    1. 81479,

    2. 81460 and 81465

    Not Provided

    81479x1 (Sanger)

    81465x1,

    81460x1

    Turnaround Time

    2-4 weeks (10-14 days typical)

    2-4 weeks (Test 453);

    3-4 weeks (Test 554)

    10 days (Variant);

    28 days (NGS)

    Cost per Test

    Not Provided

    $250-$3,000 (Varies by payer/test)

    $540 (Variant) (·Cost: the cost we got from Pathology at Texas Children's Hospital is $540. At least this could potentially be billed through insurance);

    $2,000-$3,000 (NGS)

    Contact and Lab Director

    Jing Wang, PhD;

    dgdgeneticcounselor@chop.edu

    Renkui Bai, PhD

    rbai@genedx.com

    Yue Wang, PhD;

    ywang@baylorgenetics.com

    Test URL

    https://www.testmenu.com/CHOP/Tests/1107280

    https://providers.genedx.com/tests/detail/mito-genome-sequencing-deletion-testing-508 ( Mito Genome Sequencing & Deletion Testing Test code 554)

    https://providers.genedx.com/tests/detail/known-mtdna-variant-s-by-ngs-test-453-802  (Known mtDNA Variant(s) by NGS-Test 453)

    https://catalog.baylorgenetics.com/search?keywords=3056

    https://catalog.baylorgenetics.com/search?keywords=2055

     * Please contact the labs to inquiry for the updated tests and costs.

    Additional Genetic Testing Providers: Genetic Testing Registry (GTR) at NCBI: Clinical and research tests for mitochondrial   



    2. Genetic Testing Data Analysis Resources for T11232C (m.11232T>C) Variant and Relevant Haplogroup(s)

    MSeqDR - Phy-Mer and mvTool for Haplogroup Calling and Variant Annotation   

    Haplogrep - mtDNA Haplogroup Classification Service   
    ** For users who have mtDNA genome raw data and want to check for themselves what the haplogroup may be.

    T11232C Work Group

    Introduction

    This expert panel was formed to address the emerging safety concern of severe anesthetic hypersensitivity in individuals of Indigenous American ancestry carrying the mitochondrial DNA variant m.11232T>C.

    The panel's core objectives are to:
    1. Collect and critically evaluate all relevant clinical and scientific evidence.
    2. Develop formal, evidence-based guidelines for clinical genetic testing.
    3. Compile a directory of clinical genetic testing resources and providers.

    Members

    Marni J Falk
    Mira Irons
    Richard J Levy
    Philip Morgan
    Fernando Scaglia
    Theodore Schurr
    Lishuang Shen
    Xiaowu Gai
    Renkui Bai
    Philip Yeske
    Elizabeth M Mccormick
    Yue Wang


    Internal Content

    Internal content is open to the group memebers. Please Logon.

    Upload and Share Data and Documents.

    Access the Shared Data and Documents:
       (To be added, must logon as T11232C Work Group member).

    Please contact us at the MSeqDR feedback and email page if you have any information or resources to share, or if you have any questions or concerns.