Computational protocol: Malignant hyperthermia: a review

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Protocol publication

[…] Whole exome or targeted exon NGS is becoming the preferred option for variant detection and is being used diagnostically. The vast numbers of identified variants of unknown significance (VUS), which may or may not be associated with a certain disease have to be filtered. This is a significant bottleneck in DNA-based diagnosis for MH because of the large size of the RYR1 gene, the large number of known uncharacterized variants and the technical difficulty involved with functional analysis. To be able to predict accurately the pathogenicity for a specific variant would considerably aid diagnosis and prevention of MH episodes.There are many bioinformatic tools freely available (for example PolyPhen2 [], Pmut [], SIFT [], MutPred [] and SNPs&GO [] that allow pathogenicity prediction of VUS. The accuracy of the predictions however, varies from program to program. Some of them have been trained on mutations in the on-line mendelian inheritance in man (OMIM) and human genome mutation database (HGMD) repositories, whereas others predict pathogenicity according to sequence homology of ortholog proteins.PolyPhen2 scores are displayed in the Exome Variant Server (EVS) while both PolyPhen and SIFT scores are provided in the 1000 genomes browser. According to all the available information about a variant from the literature, genome databases as well as bioinformatic analysis and segregation analysis, the variants are classed into “definitively benign, probably benign, uncertain pathogenicity, probably pathogenic and definitely pathogenic” []. There is always a degree of uncertainty with any in silico analysis. While such predictions are useful in selecting variants for functional analysis it would be premature to begin using them for clinical diagnosis of MH susceptibility.In summary, because of the heterogeneity of the disorder, as well as discordance within families, a negative DNA result cannot be used to rule out MH susceptibility. In addition, only those variants that have been biochemically characterized to affect SR Ca2+ release can be used to test for MH susceptibility. […]

Pipeline specifications

Software tools PolyPhen, PMut, SIFT, MutPred, SNPs&GO
Application WES analysis
Organisms Homo sapiens, Sus scrofa, Canis lupus familiaris, Equus caballus
Diseases Acidosis, Muscular Diseases, Rhabdomyolysis, Genetic Diseases, Inborn
Chemicals Caffeine, Calcium, Carbon Dioxide, Dantrolene, Halothane, Isoflurane, Oxygen, Ryanodine, Succinylcholine