Presence of Two Different Genetic Traits in Malignant Hyperthermia Families

Monnier, Nicole; Krivosic-Horber, R; Payen, Jean‐François; Kozak‐Ribbens, G.; Nivoche, Y.; Adnet, P.; Reyford, H.; Lunardi, Joël

doi:10.1097/00000542-200211000-00007

Cited by 180 publications

(39 citation statements)

References 25 publications

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“…Over 100 RyR1 mutations have been associated with MH, involving inappropriate activation of RyR1, which causes uncontrolled release of SR Ca 2+ and muscle contractions. MH occurs at a rate of 1:50,000–100,000 adults and 1:15,000 children undergoing anesthesia; some studies have suggested a much more frequent rate of 1:5000 adults with MH susceptible mutations occurring at 1:3000 (Rosenberg et al 2007; Monnier et al 2002). The exact prevalence of MH susceptibility is difficult to determine since the syndrome only becomes apparent after exposure to triggering agents including volatile anesthetic agents such as halothane, isoflurane, sevoflurane, desflurane, enflurane and the neuromuscular blocking agent succinylcholine (Larach 2007).…”

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 99%

Physiology and pathophysiology of excitation–contraction coupling: the functional role of ryanodine receptor

Santulli

Lewis

Marks

2017

J Muscle Res Cell Motil

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Calcium (Ca2+) release from intracellular stores plays a key role in the regulation of skeletal muscle contraction. The type 1 ryanodine receptors (RyR1) is the major Ca2+ release channel on the sarcoplasmic reticulum (SR) of myocytes in skeletal muscle and is required for excitation-contraction (E–C) coupling. This article explores the role of RyR1 in the skeletal muscle physiology and pathophysiology.

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Section: Malignant Hyperthermia (Mh)mentioning

confidence: 99%

Physiology and pathophysiology of excitation–contraction coupling: the functional role of ryanodine receptor

Santulli

Lewis

Marks

2017

J Muscle Res Cell Motil

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“…The prevalence of genetic variants predisposing to MH has been estimated to be as high as 1:2,000 1,2 . In most families MH shows an autosomal dominant pattern of inheritance.…”

Section: Introductionmentioning

confidence: 99%

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness

et al. 2015

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Background Variants in RYR1 are associated with the majority of cases of malignant hyperthermia (MH), a form of heat illness pharmacogenetically triggered by general anesthetics, and they have also been associated with exertional heat illness. CACNA1S has also been implicated in MH. We applied a targeted next generation sequencing approach to identify variants in RYR1 and CACNA1S in a cohort of unrelated patients diagnosed with MH susceptibility. We also provide the first comprehensive report of sequencing of these two genes in a cohort of survivors of exertional heat illness. Methods DNA extracted from blood was genotyped using a “long” polymerase chain reaction technique, with sequencing on the Illumina GAII® or MiSeq® platforms (Illumina Inc., San Diego, CA). Variants were assessed for pathogenicity using bioinformatic approaches. For further follow up DNA from additional family members and up to 211 MH normal and 556 MH susceptible unrelated individuals was tested. Results In 29 MH patients we identified three pathogenic and four novel RYR1 variants, with a further five RYR1 variants previously reported in association with MH. Three novel RYR1 variants were found in the exertional heat illness cohort (n = 28) along with two more previously reported in association with MH. Two other variants were reported previously associated with centronuclear myopathy. We found one and three rare variants of unknown significance in CACNA1S in the MH and exertional heat illness cohorts respectively. Conclusion Targeted next generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and exertional heat illness.

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“…The published prevalence of MHS mutations varies widely from 1 in 2,000 1,32 to 1/10,000 4 but the penetrance has been difficult to determine. Our study of 870 exomes, although it represents a prodigious amount of data, is still too small to estimate the prevalence of MHS.…”

Section: Discussionmentioning

confidence: 99%

Using Exome Data to Identify Malignant Hyperthermia Susceptibility Mutations

Gonsalves¹,

Ng²,

Johnston³

et al. 2013

Anesthesiology

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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. Our aim 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 We identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but we excluded synonymous variants. In RYR1, we 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 us to be 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.

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Presence of Two Different Genetic Traits in Malignant Hyperthermia Families

Cited by 180 publications

References 25 publications

Physiology and pathophysiology of excitation–contraction coupling: the functional role of ryanodine receptor

Physiology and pathophysiology of excitation–contraction coupling: the functional role of ryanodine receptor

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness

Using Exome Data to Identify Malignant Hyperthermia Susceptibility Mutations

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