Malignant Hyperthermia Registry and Genetic Testing

Study Overview
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Brief Summary
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The purpose of this study is to to determine the penetrance of known and probable pathogenic variants in genes and the factors that contribute to penetrance in a population of children and adults in the United States exposed to Malignant Hyperthermia (MH) trigger agents.

Detailed Description
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The purpose of the study is to determine how genetic mutations and variants in combination with non-genetic factors influence risk for MH in children who had general anesthesia with triggering agents and develop reliable predictive MH risk algorithms. Rationale: Once the factors responsible for MH risk are determined, it will be possible to better predict risk and develop better individualization of anesthetics such as tailored selection of intravenous anesthetics, regional anesthesia and avoidance of all triggering agents. The long-term goal is to tailor and improve safety of anesthetic and clinical care and to reduce mortality, morbidity and cost of care due to MH with right anesthetics and muscle relaxants for endotracheal intubations for an individual child.

Official Title
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Donation of Blood for Genetic Testing With Clinical Data From the North American Malignant Hyperthermia Registry

Conditions
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Malignant Hyperthermia

Intervention / Treatment
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* Genetic: Whole exome sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any English speaking person registered at NAHMR who has had a positive clinical manifestation of Malignant Hyperthermia Any person with a positive Caffeine Halothane Contracture probTest (CHCT) or a close relative of a person that had these. Exclusion Criteria: Any person who has NOT had a positive clinical manifestation of Malignant Hyperthermia Any person with a positive Caffeine Halothane Contracture Test (CHCT) or NOT a close relative of a person that had these. Non-English speaking registrants will be excluded.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Malignant Hyperthermia Phenotype cases<br>Samples from persons who identify as having the malignant hyperthermia phenotype by the North American MH Registry (NAMHR) | Genetic: Whole exome sequencing<br>* DNA sequencing of protein coding sections of all genes<br>|
| Caffeine Halothane Contracture Test negative controls<br>Controls who had negative Caffeine Halothane Contracture Test (CHCT) from North American MH Registry (NAMHR) | Genetic: Whole exome sequencing<br>* DNA sequencing of protein coding sections of all genes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genetic comparison of MH phenotype subjects to that of the CHCT negative control subjects. | MHS subjects and CHCT negative controls recruited from the North American MH Registry will have whole genome sequencing | Within data collection period (5 years total). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genomic factors that influence Malignant Hyperthermia. | A Batesian inference algorithm based on multiple genetic risk factors assessed from DNA data collected | Within data collection period (5 years total). | 
| Induced pluripotent stem cells will be used for functional testing and gene editing | Induced pluripotent stem cells will be made for future in-vitro analysis | Indefinite - dependent on funding | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malignant, genetics, RYR1, CAC-NA1S, hyperthermia