RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms.
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ABSTRACT: Aim
To examine the genetic differences between subjects with statin-associated muscle symptoms and statin-tolerant controls.Materials & methods
Next-generation sequencing was used to characterize the exomes of 76 subjects with severe statin-associated muscle symptoms and 50 statin-tolerant controls.Results
12 probably pathogenic variants were found within the RYR1 and CACNA1S genes in 16% of cases with severe statin-induced myopathy representing a fourfold increase over variants found in statin-tolerant controls. Subjects with probably pathogenic RYR1 or CACNA1S variants had plasma CK 5X to more than 400X the upper limit of normal in addition to having muscle symptoms.Conclusions
Genetic variants within the RYR1 and CACNA1S genes are likely to be a major contributor to the susceptibility to statin-associated muscle symptoms.
SUBMITTER: Isackson PJ
PROVIDER: S-EPMC6563124 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
Publications
RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms.
Isackson Paul J PJ Wang Jianxin J Zia Mohammad M Spurgeon Paul P Levesque Adrian A Bard Jonathan J James Smitha S Nowak Norma N Lee Tae Keun TK Vladutiu Georgirene D GD
Pharmacogenomics 20181016 16
<h4>Aim</h4>To examine the genetic differences between subjects with statin-associated muscle symptoms and statin-tolerant controls.<h4>Materials & methods</h4>Next-generation sequencing was used to characterize the exomes of 76 subjects with severe statin-associated muscle symptoms and 50 statin-tolerant controls.<h4>Results</h4>12 probably pathogenic variants were found within the RYR1 and CACNA1S genes in 16% of cases with severe statin-induced myopathy representing a fourfold increase over v ...[more]
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Project description:BackgroundMalignant hyperthermia (MH) is a pharmacogenetic disorder that has been linked to the skeletal muscle calcium release channel (RYR1) and the α1S subunit of the voltage-dependent L-type calcium channel (CACNA1S). Genomic DNA capture and next generation sequencing are becoming the preferred method to identify mutations in these genes. Bioinformatic pathogenicity prediction of identified variants may help to determine if these variants are in fact disease causing.MethodsEight pathogenicity prediction programmes freely available on the web were used to determine their ability to correctly predict the impact of a missense variant on RyR1 or dihydropyridine receptor (DHPR) protein function. We tested MH-causative variants, variants that had been shown to alter calcium release in cells, and common sequence variants in RYR1 and CACNA1S.ResultsNone of the prediction programmes was able to identify all of the variants tested correctly as either 'damaging' (MH-causative variants, variants that had been shown to alter calcium release in cells) or as 'benign' (common sequence variants). The overall sensitivity of predictions ranged from 84% to 100% depending on the programme used, with specificity from 25% to 83%.ConclusionsIn this study we determined the sensitivity and specificity of bioinformatic pathogenicity prediction tools for RYR1 and CACNA1S. We suggest that the prediction results should be treated with caution, as none of the programmes tested predicted all the variants correctly and should only be used in combination with other available data (functional assays, segregation analysis).
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Project description: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 (EHI). CACNA1S has also been implicated in MH. The authors applied a targeted next-generation sequencing approach to identify variants in RYR1 and CACNA1S in a cohort of unrelated patients diagnosed with MH susceptibility. They also provide the first comprehensive report of sequencing of these two genes in a cohort of survivors of EHI. 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., USA). 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, the authors 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 EHI cohort (n = 28) along with two more previously reported in association with MH. Two other variants were reported previously associated with centronuclear myopathy. The authors found one and three rare variants of unknown significance in CACNA1S in the MH and EHI cohorts, respectively. CONCLUSIONS:Targeted next-generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and EHI.
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