Assessing the pathogenicity of RYR1 variants in malignant hyperthermia.

@article{Merritt2017AssessingTP,
  title={Assessing the pathogenicity of RYR1 variants in malignant hyperthermia.},
  author={A Merritt and Patrick Booms and M‐A. Shaw and D. M. Miller and Catherine Daly and Jonathan G. Bilmen and Kathryn M. Stowell and Paul D. Allen and Derek Steele and Philip M Hopkins},
  journal={British journal of anaesthesia},
  year={2017},
  volume={118 4},
  pages={
          533-543
        }
}
Background . Missense variants in the ryanodine receptor 1 gene ( RYR1 ) are associated with malignant hyperthermia but only a minority of these have met the criteria for use in predictive DNA diagnosis. We examined the utility of a simplified method of segregation analysis and a functional assay for determining the pathogenicity of recurrent RYR1 variants associated with malignant hyperthermia. Methods . We identified previously uncharacterised RYR1 variants found in four or more malignant… 
Relevance of pathogenicity prediction tools in human RYR1 variants of unknown significance
TLDR
Blood samples from 235 individuals with a history of a clinical malignant hyperthermia or their close relatives were genetically screened for RYR1 variants of all 106 RYP1 exons and additionally for known variants of CACNA1S to examine whether freely available pathogenicity prediction tools are able to detect relevant MH causing variants.
Genetic epidemiology of malignant hyperthermia in the UK
Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia
TLDR
The pathogenicity of four C-terminal variants of the ryanodine receptor using functional analysis was assessed, finding that the p.Val4849Ile variant should be considered a risk factor for malignant hyperthermia and two variants should be classified as pathogenic for central core disease.
Next-generation sequencing and bioinformatics to identify genetic causes of malignant hyperthermia.
Defining molecular mechanisms of calcium dysregulation in malignant hyperthermia susceptibility
TLDR
Next generation sequencing of fifty genes associated with Ca2+ handling, performed by the Leeds MH Unit, identified two calsequestrin-1 (CASQ1) variants, p.I138T and p.F186Y, in an MH individual and an exertional heat illness (EHI) individual, respectively, which suggest that the highly conserved CASQ1 p.
An unusual ryanodine receptor 1 (RYR1) phenotype
TLDR
The spectrum of RYR1-related disorders is expanded to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance, which is a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis.
Malignant hyperthermia: still an issue for neuromuscular diseases?
TLDR
An overview of neuromuscular disorders that can be linked with malignantHyperthermia or malignant hyperthermia-like reactions, and an appropriate approach to interpret the risks are suggested to determine which patients are at risk of malignanthyperthermia and malignant Hyperthermia perioperatively and to ensure adequate treatment in case such an acute complication occurs.
Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990–2019
TLDR
Findings from these studies have set the foundation for therapeutic development for MH and RYR1 -RM, a spectrum of rare neuromuscular disorders, which have been developed to better understand underlying pathomechanisms and test potential therapeutics.
Malignant Hyperthermia and Gene Polymorphisms Related to Inhaled Anesthesia Drug Response
TLDR
Gene analysis testing is recommended for diagnosing patient with MH medical history or MH patient’s relations, as scientists have found that from 37% to 86% of MH cases have RYR1 mutations and approximately 1% of those have CACNA1S mutations.
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References

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TLDR
It is proposed that R2355W is confirmed as being an MH-causative mutation and suggested that V2354M is a RYR1 mutation likely to cause MH.
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TLDR
Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke.
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TLDR
Exome sequencing can identify asymptomatic patients at risk for MHS, although the interpretation of exome variants can be challenging.
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TLDR
Performing an in‐depth mutation screening of the RYR1 transcript sequence in 36 unrelated MH susceptible (MHS) patients, this study identified 17 novel, five rare, and eight non‐disease‐causing variants in 23 patients.
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The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation–contraction coupling and skeletal muscle calcium homeostasis. Mapping to
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TLDR
This study successfully demonstrates the use of genomic DNA capture and next-generation sequencing for identification of putative mutations causing malignant hyperthermia and suggests that whole exome sequencing may be necessary to identify MH causing mutations in patients where no mutations in RYR1 and CACNA1S have been identified thus far.
Exome Sequencing Reveals Novel Rare Variants in the Ryanodine Receptor and Calcium Channel Genes in Malignant Hyperthermia Families
TLDR
Using both exome sequencing and allele frequency data from large sequencing efforts may aid genetic diagnosis of malignant hyperthermia, and this technique was more sensitive for variant detection in known genes than Sanger sequencing of complementary DNA, and allows for the possibility of novel gene discovery.
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TLDR
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TLDR
Targeted next-generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and EHI.
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