Variant landscape of the RYR1 gene based on whole genome sequencing of the Singaporean population.
Variant landscape of the RYR1 gene based on whole genome sequencing of the Singaporean population.
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DOI：
10.1038/s41598-022-09310-w
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发表时间：
2022-03-31
影响因子：
4.6
通讯作者：
Ti LK
中科院分区：
文献类型：
--
作者：
Foo CTY;To YH;Irwanto A;Ng AY;Yan B;Chew STH;Liu J;Ti LK
RYR 1基因编码兰尼碱受体，其是骨骼肌肌浆网中的钙释放通道。它与恶性高热（MH）和先天性肌病（包括中央核心病（CCD）、多微核心病（MMD）和先天性纤维型不比例（CFTD））有关。目前关于亚洲人中RYR 1变体的流行病学信息很少。我们的研究旨在描述RYR 1变异景观在新加坡队列研究RYR 1相关的条件。从SG 10 K试点项目中检索数据，其中对RYR 1相关疾病的志愿者进行了全基因组测序。使用数据库ClinVar和InterVar基于致病性对变体进行分类。比较了中国人、印度人和马来人致病性变异的等位基因频率。使用数据库ExAC，GnomAD和GenomeAsia 100 k study，我们进一步比较了当地等位基因频率与欧洲，美洲和亚洲的等位基因频率。使用R Commander分析数据。显著P值设定为p < 0.05。大多数RYR 1变异体是错义突变。我们确定了四种致病性和四种可能致病的RYR 1变体。所有这些都与上述RYR 1相关的疾病有关。在4810名个体中有6名携带RYR 1致病性变异体，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（4/1127）（p = 0.030）。大多数致病性和可能致病性突变是错义突变，位于突变热点。这些变异在亚洲人中的发生频率也高于全球。这项研究描述了变异景观的RYR 1基因在新加坡。这些知识将有助于RYR 1相关疾病的遗传筛查。
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.
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