Epigenetic allele silencing and variable penetrance of malignant hyperthermia susceptibility

MH Investigation Unit, Academic Unit of Anaesthesia, St James's University Hospital, Leeds LS9 7TF, UK.
BJA British Journal of Anaesthesia (Impact Factor: 4.85). 06/2009; 103(2):220-5. DOI: 10.1093/bja/aep108
Source: PubMed


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.
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.
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.
Epigenetic allele silencing may play a role in the inheritance of MH susceptibility, but this is unlikely to involve silencing of RYR1.

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    • "In the remaining cases, the ER/MHS phenotype could be caused by RYR1 SVs which may escape the RYR1 cDNA screening because they determine unbalanced allelic expression [43] [44] [45] [46] or, alternatively, could be caused by mutations in other candidate MHS loci genes. "
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