title: Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy.
abstract: Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.
authors.affiliation: Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Kraeva
authors.affiliation: Laboratory of Neurogenetics and Biobank, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; Laboratory of Ultrastructural Neuropathology and Biobank, Institute Born-Bunge (IBB), University of Antwerp, Antwerpen, Belgium; MH Research Unit, University of Antwerp, Antwerpen, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Heytens
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK; Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College London, London, UK; Department of Clinical and Basic Neuroscience, IoPPN, King's College London, London, UK; Children's Neuroscience Centre, St Thomas' Hospital, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Jungbluth
authors.affiliation: Departments of Anesthesia and Biomedizin, ZLF Lab 408, Universitätsspital Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Treves
authors.affiliation: Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Voermans
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Kamsteeg
authors.affiliation: Laboratory of Ultrastructural Neuropathology and Biobank, Institute Born-Bunge (IBB), University of Antwerp, Antwerpen, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Ceuterick-de Groote
authors.affiliation: Laboratory of Neurogenetics and Biobank, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; Department of Neurology, University Hospital Antwerp, Belgium; Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Baets
authors.affiliation: Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, ON, Canada; Department of Anesthesia and Pain Management, University of Toronto, Toronto, ON, Canada. Electronic address: Sheila.Riazi@uhn.on.ca.
authors.forename: S
authors.initials: S
authors.lastname: Riazi
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D007866:Leg / Q000473:pathology; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020512:Myopathy, Central Core / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Compound RYR1 heterozygosity; Core myopathies; Malignant hyperthermia