title: Next-generation DNA sequencing of a Swedish malignant hyperthermia cohort.
abstract: Malignant hyperthermia (MH)-related mutations have been identified in the ryanodine receptor type 1 gene (RYR1) and in the dihydropyridine gene (CACNA1S), but about half of the patients do not have causative mutations in these genes. We wanted to study the contribution of other muscle genes to the RYR1 phenotypes. We designed a gene panel for sequence enrichment targeting 64 genes of proteins involved in the homeostasis of the striated muscle cell. Next-generation sequencing (NGS) resulted in >50,000 sequence variants which were further analyzed by software filtering criteria to identify causative variants. In four of five patients we identified previously reported RYR1 mutations while the fifth patient did not show any candidate variant in any of the genes investigated. In two patients pathogenic variants were found in other genes known to cause a muscle disorders. All but one patient carried likely benign rare polymorphisms. The NGS technique proved convenient in identifying variants in the RYR1. However, with a clinically variable phenotype-like MH, the pre-selection of genes poses problems in variant interpretation.
authors.affiliation: Department of Perioperative and Intensive Care, Skåne University Hospital, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Broman
authors.affiliation: Institute of Human Genetics, Biocentre, University of Würzburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Kleinschnitz
authors.affiliation: Institute of Human Genetics, Biocentre, University of Würzburg, Germany.
authors.forename: J E
authors.initials: JE
authors.lastname: Bach
authors.affiliation: Institute of Human Genetics, Biocentre, University of Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Rost
authors.affiliation: Department of Perioperative and Intensive Care, Skåne University Hospital, Lund, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Islander
authors.affiliation: Institute of Human Genetics, Biocentre, University of Würzburg, Germany.
authors.forename: C R
authors.initials: CR
authors.lastname: Müller
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
keywords: malignant hyperthermia; muscle; mutation; next-generation sequencing