title: Epigenetic allele silencing and variable penetrance of malignant hyperthermia susceptibility.
abstract: BACKGROUND
  Tissue-specific monoallelic silencing of the RYR1 gene has been proposed as an explanation for variable penetrance of dominant RYR1 mutations in malignant hyperthermia (MH). We examined the hypothesis that monoallelic silencing could explain the inheritance of an MH discordant phenotype in some instances.
  
  
  METHODS
  We analysed parent-offspring transmission data from MH kindreds to assess whether there was any deviation from the expected autosomal dominant Mendelian inheritance pattern. We also evaluated informative single-nucleotide polymorphism (SNP) genotypes in a cohort of unrelated MH patients using genomic DNA (gDNA, prepared from leucocytes) and coding DNA (cDNA, prepared from skeletal muscle). Finally, we examined the segregation of specific mutations at the gDNA and cDNA level within MH families where positive RYR1 gDNA genotype/normal MH phenotype discordance had been observed.
  
  
  RESULTS
  In 2113 transmissions from affected parents, there was a consistent parent-of-origin effect (P<0.001) with affected fathers having fewer affected daughters (20%, 95% CI 17-22%) than affected sons (25%, 95% CI 23-26%) or unaffected daughters (27%, 95% CI 25-30%). No discrepancies were observed between the RYR1 SNP genotypes recorded at the gDNA and cDNA levels. In 14 MH negative individuals from 11 discordant families, the familial mutation was detected in skeletal muscle cDNA in all cases.
  
  
  CONCLUSIONS
  Epigenetic allele silencing may play a role in the inheritance of MH susceptibility, but this is unlikely to involve silencing of RYR1.
authors.affiliation: MH Investigation Unit, Academic Unit of Anaesthesia, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: R L
authors.initials: RL
authors.lastname: Robinson
authors.forename: D
authors.initials: D
authors.lastname: Carpenter
authors.forename: P J
authors.initials: PJ
authors.lastname: Halsall
authors.forename: D E
authors.initials: DE
authors.lastname: Iles
authors.forename: P
authors.initials: P
authors.lastname: Booms
authors.forename: D
authors.initials: D
authors.lastname: Steele
authors.forename: P M
authors.initials: PM
authors.lastname: Hopkins
authors.forename: M-A
authors.initials: MA
authors.lastname: Shaw
mesh_terms: D015331:Cohort Studies; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D018482:Muscle, Skeletal / Q000737:chemistry; D019683:Penetrance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel