Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants

Pharmacogenomics. 2019 Sep;20(14):989-1003. doi: 10.2217/pgs-2019-0055.

Abstract

Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.

Keywords: CACNA1S; RYR1; STAC3; contracture test; exome; genetic; malignant hyperthermia; muscle; next-generation sequencing; novel; pathologic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Bayes Theorem
  • Calcium Channels, L-Type / genetics*
  • Disease Susceptibility
  • Exome Sequencing
  • Exons / genetics
  • Female
  • Genetic Variation / genetics
  • Genotype
  • Humans
  • Male
  • Malignant Hyperthermia / genetics*
  • Malignant Hyperthermia / pathology
  • Mutation / genetics
  • Ryanodine Receptor Calcium Release Channel / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • CACNA1S protein, human
  • Calcium Channels, L-Type
  • RYR1 protein, human
  • Ryanodine Receptor Calcium Release Channel
  • Stac3 protein, human