Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Nalagenetics Pte. Ltd, Singapore, Singapore.
Sci Rep. 2022 Mar 31;12(1):5429. doi: 10.1038/s41598-022-09310-w.
The RYR1 gene codes for a ryanodine receptor which is a calcium release channel in the skeletal muscle sarcoplasmic reticulum. It is associated with Malignant Hyperthermia (MH) and congenital myopathies including Central Core Disease (CCD), Multiminicore Disease (MMD) and Congenital Fibre-Type Disproportion (CFTD). There is currently little information on the epidemiology of RYR1 variants in Asians. Our study aims to describe the RYR1 variant landscape in a Singapore cohort unselected for RYR1-associated conditions. Data was retrieved from the SG10K pilot project, where whole genome sequencing was performed on volunteers unselected and undetermined for RYR1-associated conditions. Variants were classified based on pathogenicity using databases ClinVar and InterVar. Allele frequencies of pathogenic variants were compared between Chinese, Indians and Malays. Using databases ExAC, GnomAD and GenomeAsia 100k study, we further compared local allele frequencies to those in Europe, America and Asia. Data was analysed using R Commander. Significant P value was set at p < 0.05. Majority of the RYR1 variants were missense mutations. We identified four pathogenic and four likely pathogenic RYR1 variants. All were related to the aforementioned RYR1-associated conditions. There were 6 carriers of RYR1 pathogenic variants amongst 4810 individuals, corresponding to an allele frequency of 0.06%. The prevalence of pathogenic variants was the highest amongst Indians (4 in 1127 individuals) (p = 0.030). Majority of pathogenic and likely pathogenic mutations were missense and located in mutational hotspots. These variants also occurred at higher frequencies in Asians than globally. This study describes the variant landscape of the RYR1 gene in Singapore. This knowledge will facilitate genetic screening for RYR1-related conditions.
RYR1 基因编码一种肌质网钙离子释放通道 Ryanodine 受体。它与恶性高热(MH)和先天性肌病有关,包括中央核疾病(CCD)、多肌病(MMD)和先天性纤维型比例失调(CFTD)。目前亚洲人 RYR1 变异的流行病学信息很少。我们的研究旨在描述新加坡队列中未选择与 RYR1 相关疾病的 RYR1 变异景观。数据来自 SG10K 试点项目,该项目对未选择和未确定与 RYR1 相关疾病的志愿者进行全基因组测序。根据 ClinVar 和 InterVar 数据库,根据致病性对变异进行分类。在中国人、印度人和马来人之间比较致病性变异的等位基因频率。使用 ExAC、GnomAD 和 GenomeAsia 100k 研究数据库,我们进一步将当地的等位基因频率与欧洲、美洲和亚洲进行比较。使用 R Commander 进行数据分析。显著 P 值设置为 p < 0.05。大多数 RYR1 变异是错义突变。我们确定了 4 个致病性和 4 个可能致病性的 RYR1 变异。所有这些都与上述 RYR1 相关疾病有关。在 4810 名个体中,有 6 名个体携带 RYR1 致病性变异,对应的等位基因频率为 0.06%。致病性变异的患病率在印度人中最高(1127 人中 4 例)(p = 0.030)。大多数致病性和可能致病性的突变是错义突变,位于突变热点。这些变异在亚洲的发生率也高于全球。本研究描述了新加坡 RYR1 基因的变异景观。这一知识将有助于 RYR1 相关疾病的遗传筛查。
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