Allele-specific differences in ryanodine receptor 1 mRNA expression levels may contribute to phenotypic variability in malignant hyperthermia

<p>Abstract</p> <p>Background</p> <p>Malignant hyperthermia (MH) is a dominantly inherited skeletal muscle disorder that can cause a fatal hypermetabolic reaction to general anaesthetics. The primary locus of MH (MHS1 locus) in humans is linked to chromosome 19q13.1, the position of the gene encoding the ryanodine receptor skeletal muscle calcium release channel (RyR1).</p> <p>Methods</p> <p>In this study, an inexpensive allele-specific PCR (AS-PCR) assay was designed that allowed the relative quantification of the two RyR1 transcripts in heterozygous samples found to be susceptible to MH (MHS). Allele-specific differences in RyR1 expression levels can provide insight into the observed variable penetrance and variations in MH phenotypes between individuals. The presence/absence of the H4833Y mutation in <it>RYR</it>1 transcripts was employed as a marker that allowed discrimination between the two alleles.</p> <p>Results</p> <p>In four skeletal muscle samples and two lymphoblastoid cell lines (LCLs) from different MHS patients, the wild type allele was found to be expressed at higher levels than the mutant RyR1 allele. For both LCLs, the ratios between the wild type and mutant <it>RYR</it>1 alleles did not change after different incubation times with actinomycin D. This suggests that there are no allele-specific differences in RyR1 mRNA stability, at least in these cells.</p> <p>Conclusion</p> <p>The data presented here revealed for the first time allele-specific differences in <it>RYR</it>1 mRNA expression levels in heterozygous MHS samples, and can at least in part contribute to the observed variable penetrance and variations in MH clinical phenotypes.</p

The Future of Precision Medicine : Potential Impacts for Health Technology Assessment

Objective Precision medicine allows health care interventions to be tailored to groups of patients based on their disease susceptibility, diagnostic or prognostic information or treatment response. We analyse what developments are expected in precision medicine over the next decade and consider the implications for health technology assessment (HTA) agencies. Methods We perform a pragmatic review of the literature on the health economic challenges of precision medicine, and conduct interviews with representatives from HTA agencies, research councils and researchers from a variety of fields, including digital health, health informatics, health economics and primary care research. Results Three types of precision medicine are highlighted as likely to emerge in clinical practice and impact upon HTA agencies: complex algorithms, digital health applications and ‘omics’-based tests. Defining the scope of an evaluation, identifying and synthesizing the evidence and developing decision analytic models will more difficult when assessing more complex and uncertain treatment pathways. Stratification of patients will result in smaller subgroups, higher standard errors and greater decision uncertainty. Equity concerns may present in instances where biomarkers correlate with characteristics such as ethnicity, whilst fast-paced innovation may reduce the shelf-life of guidance and necessitate more frequent reviewing. Discussion Innovation in precision medicine promises substantial benefits to patients, but will also change the way in which some health services are delivered and evaluated. As biomarker discovery accelerates and AI-based technologies emerge, the technical expertise and processes of HTA agencies will need to adapt if the objective of value for money is to be maintained