Malignant Hyperthermia Registry and Genetic Testing

Title: 
Malignant Hyperthermia Registry and Genetic Testing
Recruitment Status: 
Terminated
Status Last Updated: 
June 15, 2021
Clinical Phenotype(s): 
Malignant Hyperthermia susceptibility - MHS1 (RYR1)
Gene(s): 
RYR1
Study Purpose: 

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.

Phase: 
Unknown
Study Description: 

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.

Study Type: 
Observational
Official Title: 
Donation of Blood for Genetic Testing With Clinical Data From the North American Malignant Hyperthermia Registry
Study Start Date: 
August 2015
Study Completion Date: 
August 2020
Primary Objective(s): 
  1. Genetic comparison of MH phenotype subjects to that of the CHCT negative control subjects. [ Time Frame: Within data collection period (5 years total). ]
  • MHS subjects and CHCT negative controls recruited from the North American MH Registry will have whole genome sequencing
Secondary Objective(s): 
  1. Genomic and demographic factors that influence Malignant Hyperthermia. [ Time Frame: Within data collection period (5 years total). ]
  2. A diagnostic predictive algorithm based on multiple genetic and other risk factors assessed from DNA data collected on NAMHR subjects and CCHMC subjects will be used to differentiate MH influences.
  3. Isolate DNA from blood samples to obtain information [ Time Frame: Within data collection period (5 years total). ]
  4. Blood samples will be used to obtain DNA methylation information by measuring CpG sites in important genes (RYR1, CACNA1S, STAC3 and other MH relevant genes) and/or use of the MethylationEPIC array.
  5. Induced pluripotent stem cells will be used for functional testing and gene editing [ Time Frame: Within data collection period (5 years total). ]
  6. Induced pluripotent stem cells will be differentiated into skeletal muscle cells and functional testing of the ryanodine receptor will be performed. In addition, gene editing using CRISPR technology will be performed to edit/delete variants of uncertain significance.
  7. Differences in expression of MH related genes will be assessed by RNA sequencing [ Time Frame: Within data collection period (5 years total). ]
  8. RYR1 (and other MH related genes) in MH phenotype cases and controls will be assessed by RNA sequencing.
Eligibility: 

Ages Eligible for Study: Child, Adult, Older Adult

Sexes Eligible for Study: All

Accepts Healthy Volunteers: Yes

Sampling Method: Non-Probability Sample

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.
Study Site(s)/Location(s): 

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

Sponsors & Collaborators: 

Children's Hospital Medical Center, Cincinnati

Principal Investigator(s): 

John McAuliffe, MD

For more information, please contact the Study Coordinator: 

Contact:  

Email: 

Phone: 

ClinicalTrials.gov ID: 
NCT02964481