Next-generation sequencing and bioinformatics to identify genetic causes of malignant hyperthermia
Journal
Journal of the Formosan Medical Association
Journal Volume
120
Journal Issue
2
Pages
883-892
Date Issued
2021
Author(s)
Abstract
Background/purpose: Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disease with only two known causative genes, RYR1 and CACNA1S. Both are huge genes containing numerous exons, and they reportedly only account for 50–70% of known MH patients. Next-generation sequencing (NGS) technology and bioinformatics could help delineate the genetic diagnosis of MH and several MH-like clinical presentations. Methods: We established a capture-based targeted NGS sequencing framework to examine the whole genomic regions of RYR1, CACNA1S and the 16.6 Kb mitochondrial genome, as well as 12 other genes related to excitation-contraction coupling and/or skeletal muscle calcium homeostasis. We applied bioinformatics analyses to the variants identified in this study and also to the 48 documented RYR1 pathogenic variants. Results: The causative variants were identified in seven of the eight (87.5%) MH families, but in none of the 10 individuals classified as either normal controls (N = 2) or patients displaying MH-like clinical features later found to be caused by other etiologies (N = 8). We showed that RYR1 c.1565A>G (p.Tyr522Cys)(rs118192162) could be a genetic hot spot in the Taiwanese population. Bioinformatics analyses demonstrated low population frequencies and predicted damaging effects from all known pathogenic RYR1 variants. We estimated that more than one in 1149 individuals worldwide carry MH pathogenic variants at RYR1. Conclusion: NGS and bioinformatics are sensitive and specific tools to examine RYR1 and CACNA1S for the genetic diagnosis of MH. Pathogenic variants in RYR1 can be found in the majority of MH patients in Taiwan. ? 2020
SDGs
Other Subjects
calcium channel L type; calcium channel voltage dependent L type, alpha 1s subunit; creatine kinase; dantrolene; muscle enzyme; myoglobin; ryanodine receptor 1; unclassified drug; ryanodine receptor; acidosis; adolescent; adult; aged; alkalosis; anesthesiology; aortic reconstruction; appendectomy; appendix perforation; Article; autosomal dominant inheritance; bioinformatics; bone tumor; brain damage; calcium homeostasis; cancer surgery; child; clinical article; clinical feature; colon resection; controlled study; creatine kinase blood level; dissecting aortic aneurysm; enzyme blood level; excitation contraction coupling; exon; false positive result; family history; female; fever; gene frequency; genetic screening; genetic variability; heart ventricle arrhythmia; high throughput sequencing; hip surgery; human; hyperkalemia; kidney failure; laparoscopic cholecystectomy; liver resection; male; malignant hyperthermia; masseter spasm; medical history; mitochondrial genome; muscle rigidity; muscle spasm; onset age; osteogenesis imperfecta; paralysis; pterygium; skeletal muscle; strabismus; tachycardia; Taiwanese; temperature; tibia fracture; biology; genetics; high throughput sequencing; malignant hyperthermia; mutation; Taiwan; Computational Biology; High-Throughput Nucleotide Sequencing; Humans; Malignant Hyperthermia; Mutation; Ryanodine Receptor Calcium Release Channel; Taiwan
Publisher
Elsevier B.V.
Type
journal article