Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia

2017 ◽  
Vol 49 (2) ◽  
pp. 81-87 ◽  
Author(s):  
Teresa A. Beam ◽  
Emily F. Loudermilk ◽  
David F. Kisor
Keyword(s):  
Malignant Hyperthermia ◽  
Malignant Hyperthermia Susceptibility ◽  
Incomplete Penetrance ◽  
Variable Expression ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Gated Channel ◽  
Life Threatening ◽  
Ryanodine Receptor 1 ◽  
Significant Linkage

A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S ( CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.

scholarly journals Novel SCN5A and GPD1L Variants Identified in Two Unrelated Han-Chinese Patients With Clinically Suspected Brugada Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Meng Yuan ◽  
Yi Guo ◽  
Hong Xia ◽  
Hongbo Xu ◽  
Hao Deng ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Missense Variant ◽  
Han Chinese ◽  
Chinese Patients ◽  
Splicing Variant ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Gated Channel ◽  
Life Threatening ◽  
Glycerol 3 Phosphate Dehydrogenase

Brugada syndrome (BrS) is a complexly genetically patterned, rare, malignant, life-threatening arrhythmia disorder. It is autosomal dominant in most cases and characterized by identifiable electrocardiographic patterns, recurrent syncope, nocturnal agonal respiration, and other symptoms, including sudden cardiac death. Over the last 2 decades, a great number of variants have been identified in more than 36 pathogenic or susceptibility genes associated with BrS. The present study used the combined method of whole exome sequencing and Sanger sequencing to identify pathogenic variants in two unrelated Han-Chinese patients with clinically suspected BrS. Minigene splicing assay was used to evaluate the effects of the splicing variant. A novel heterozygous splicing variant c.2437-2A>C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A>T [p.(Asp54Val)] in the glycerol-3-phosphate dehydrogenase 1 like gene (GPD1L) were identified in these two patients with BrS-1 and possible BrS-2, respectively. Minigene splicing assay indicated the deletion of 15 and 141 nucleotides in exon 16, resulting in critical amino acid deletions. These findings expand the variant spectrum of SCN5A and GPD1L, which can be beneficial to genetic counseling and prenatal diagnosis.

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

2019 ◽  
Vol 20 (14) ◽  
pp. 989-1003
Author(s):  
Senthilkumar Sadhasivam ◽  
Barbara W Brandom ◽  
Richard A Henker ◽  
John J McAuliffe
Keyword(s):  
Malignant Hyperthermia ◽  
Bayesian Statistics ◽  
Bayesian Modeling ◽  
In Silico Analysis ◽  
Malignant Hyperthermia Susceptibility ◽  
Degree Relative ◽  
New Approach ◽  
Whole Exome ◽  
Uncertain Significance ◽  
Silico Analysis

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.

scholarly journals Using Exome Data to Identify Malignant Hyperthermia Susceptibility Mutations

2013 ◽  
Vol 119 (5) ◽  
pp. 1043-1053 ◽  
Author(s):  
Stephen G. Gonsalves ◽  
David Ng ◽  
Jennifer J. Johnston ◽  
Jamie K. Teer ◽  
Peter D. Stenson ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Exome Sequencing ◽  
Malignant Hyperthermia Susceptibility ◽  
Missense Mutations ◽  
Asymptomatic Patients ◽  
Frameshift Deletion ◽  
Patients At Risk ◽  
Life Threatening ◽  
Medical Histories ◽  
Mutation Databases

Abstract Background: Malignant hyperthermia susceptibility (MHS) is a life-threatening, inherited disorder of muscle calcium metabolism, triggered by anesthetics and depolarizing muscle relaxants. An unselected cohort was screened for MHS mutations using exome sequencing. The aim of this study was to pilot a strategy for the RYR1 and CACNA1S genes. Methods: Exome sequencing was performed on 870 volunteers not ascertained for MHS. Variants in RYR1 and CACNA1S were annotated using an algorithm that filtered results based on mutation type, frequency, and information in mutation databases. Variants were scored on a six-point pathogenicity scale. Medical histories and pedigrees were reviewed for malignant hyperthermia and related disorders. Results: The authors identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but the authors excluded synonymous variants. In RYR1, the authors identified 65 missense mutations, one nonsense, two that affected splicing, and one non–frameshift indel. In CACNA1S, 48 missense, one frameshift deletion, one splicing, and one non–frameshift indel were identified. RYR1 variants predicted to be pathogenic for MHS were found in three participants without medical or family histories of MHS. Numerous variants, previously described as pathogenic in mutation databases, were reclassified by the authors as being of unknown pathogenicity. Conclusions: Exome sequencing can identify asymptomatic patients at risk for MHS, although the interpretation of exome variants can be challenging. The use of exome sequencing in unselected cohorts is an important tool to understand the prevalence and penetrance of MHS, a critical challenge for the field.

scholarly journals A Minimal-Invasive Metabolic Test Detects Malignant Hyperthermia Susceptibility in a Patient after Sevoflurane-Induced Metabolic Crisis

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Frank Schuster ◽  
Stephan Johannsen ◽  
Norbert Roewer
Keyword(s):  
Malignant Hyperthermia ◽  
Intramuscular Injection ◽  
Diagnostic Procedures ◽  
Minimal Invasive ◽  
Malignant Hyperthermia Susceptibility ◽  
Inhalation Anesthetics ◽  
Life Threatening ◽  
Life Threatening Complication ◽  
Metabolic Test

Malignant hyperthermia is a rare but life-threatening complication of general anesthesia in predisposed patients usually triggered by potent inhalation anesthetics and/or the depolarizing muscle relaxant succinylcholine. The authors present a case of delayed sevoflurane-induced malignant hyperthermia in a 21-year-old male patient that was sufficiently treated by discontinuation of trigger agent application and dantrolene infusion. After surviving an MH episode diagnostic procedures are indicated to increase patient safety. In the presented case, the use of a novel minimal-invasive metabolic test with intramuscular injection of halothane and caffeine successfully confirmed MH susceptibility and hence might be an alternative for invasive in vitro contracture testing in selected cases.

3,5-Di-t-butyl catechol is a potent human ryanodine receptor 1 activator, not suitable for the diagnosis of malignant hyperthermia susceptibility

2012 ◽  
Vol 66 (1) ◽  
pp. 80-87
Author(s):  
Caterina Lacava ◽  
Andrea Michalek-Sauberer ◽  
Birgit Kraft ◽  
Giampietro Sgaragli ◽  
Elisabeth Sipos ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Malignant Hyperthermia Susceptibility ◽  
Ryanodine Receptor 1

scholarly journals Change of Anesthesia Management for a Patient Undergoing CABG by an Incidental Finding of a Genetic Variant Associated with Malignant Hyperthermia

2019 ◽  
Vol 2019 ◽  
pp. 1-3 ◽  
Author(s):  
Trey B. Creech ◽  
Li Zhang
Keyword(s):  
Malignant Hyperthermia ◽  
Coronary Artery Bypass Surgery ◽  
Genetic Variant ◽  
Incidental Finding ◽  
Artery Bypass ◽  
Anesthesia Management ◽  
Anesthesia Providers ◽  
Whole Exome ◽  
Life Threatening ◽  
History Of

Malignant hyperthermia (MH) is a rare life-threatening hypermetabolic muscular disorder with a high mortality rate. Three genes, RYR1, CACNA1S, and STAC3, have been associated with MH susceptibility. Multiple genetic variants have been identified in these three genes. Some of those variants were pathogenic, but many others are yet to be tested. Such uncertainty can make it challenging for anesthesia providers as there is currently no anesthesia guideline for each genetic variant in patients who have neither clinical nor family history of MH. With the increasing popularity of whole exome sequencing, anesthesia providers will likely face such challenges more often as many patients may have genetic variations of unknown clinical significance in their RYR1, CACNA1S, or STAC3 genes. Here we describe change of anesthesia management for a patient who had an incidental finding of a genetic variant in RYR1 gene undergoing an elective coronary artery bypass surgery.

scholarly journals Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hui J. Wang ◽  
Chang Seok Lee ◽  
Rachel Sue Zhen Yee ◽  
Linda Groom ◽  
Inbar Friedman ◽  
...  
Keyword(s):  
Muscle Metabolism ◽  
Malignant Hyperthermia Susceptibility ◽  
Lifestyle Modifications ◽  
Release Channel ◽  
Adaptive Thermogenesis ◽  
Pathogenic Variants ◽  
Brown Adipose ◽  
Heat Response ◽  
Life Threatening ◽  
Lactate Levels

Abstract Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.

scholarly journals Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database

2021 ◽  
Author(s):  
Run Fridriksdottir ◽  
Arnar J. Jonsson ◽  
Brynjar O. Jensson ◽  
Kristinn O. Sverrisson ◽  
Gudny A. Arnadottir ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Large Fraction ◽  
Somatic Mosaicism ◽  
Missense Variant ◽  
Population Database ◽  
Pathogenic Variants ◽  
Life Threatening ◽  
Paternal Grandmother ◽  
Genetics And Genomics ◽  
Actionable Variants

AbstractMalignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband’s paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.

scholarly journals An Assessment of Penetrance and Clinical Expression of Malignant Hyperthermia in Individuals Carrying Diagnostic Ryanodine Receptor 1 Gene Mutations

2019 ◽  
Vol 131 (5) ◽  
pp. 983-991 ◽  
Author(s):  
Carlos A. Ibarra Moreno ◽  
Sally Hu ◽  
Natalia Kraeva ◽  
Frank Schuster ◽  
Stephan Johannsen ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Gene Mutations ◽  
Onset Time ◽  
Study Data ◽  
Incomplete Penetrance ◽  
Clinical Expression ◽  
Factors Affecting ◽  
Mutation Carriers ◽  
Ryanodine Receptor 1

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Malignant hyperthermia (MH) is a potentially lethal disorder triggered by certain anesthetics. Mutations in the ryanodine receptor 1 (RYR1) gene account for about half of MH cases. Discordance between the low incidence of MH and a high prevalence of mutations has been attributed to incomplete penetrance, which has not been quantified yet. The authors aimed to examine penetrance of MH-diagnostic RYR1 mutations and the likelihood of mutation carriers to develop MH, and to identify factors affecting severity of MH clinical expression. Methods In this multicenter case–control study, data from 125 MH pedigrees between 1994 and 2017 were collected from four European registries and one Canadian registry. Probands (survivors of MH reaction) and their relatives with at least one exposure to anesthetic triggers, carrying one diagnostic RYR1 mutation, were included. Penetrance (percentage of probands among all genotype-positive) and the probability of a mutation carrier to develop MH were obtained. MH onset time and Clinical Grading Scale score were used to assess MH reaction severity. Results The overall penetrance of nine RYR1 diagnostic mutations was 40.6% (93 of 229), without statistical differences among mutations. Likelihood to develop MH on exposure to triggers was 0.25 among all RYR1 mutation carriers, and 0.76 in probands (95% CI of the difference 0.41 to 0.59). Penetrance in males was significantly higher than in females (50% [62 of 124] vs. 29.7% [30 of 101]; P = 0.002). Males had increased odds of developing MH (odds ratio, 2.37; 95% CI, 1.36 to 4.12) despite similar levels of exposure to trigger anesthetics. Proband’s median age was 12 yr (interquartile range 6 to 32.5). Conclusions Nine MH-diagnostic RYR1 mutations have sex-dependent incomplete penetrance, whereas MH clinical expression is influenced by patient’s age and the type of anesthetic. Our quantitative evaluation of MH penetrance reinforces the notion that a previous uneventful anesthetic does not preclude the possibility of developing MH.

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