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基于新加坡人群全基因组测序的 RYR1 基因变异景观。

Variant landscape of the RYR1 gene based on whole genome sequencing of the Singaporean population.

机构信息

Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Nalagenetics Pte. Ltd, Singapore, Singapore.

出版信息

Sci Rep. 2022 Mar 31;12(1):5429. doi: 10.1038/s41598-022-09310-w.


DOI:10.1038/s41598-022-09310-w
PMID:35361824
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8971428/
Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5043/8971428/bc2f9b2c6481/41598_2022_9310_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5043/8971428/104d625aff87/41598_2022_9310_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5043/8971428/0947c9fcb525/41598_2022_9310_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5043/8971428/bc2f9b2c6481/41598_2022_9310_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5043/8971428/104d625aff87/41598_2022_9310_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5043/8971428/0947c9fcb525/41598_2022_9310_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5043/8971428/bc2f9b2c6481/41598_2022_9310_Fig3_HTML.jpg

相似文献

[1]
Variant landscape of the RYR1 gene based on whole genome sequencing of the Singaporean population.

Sci Rep. 2022-3-31

[2]
Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm.

Curr Opin Pharmacol. 2008-6

[3]
RYR1-Related Myopathies: Clinical, Histopathologic and Genetic Heterogeneity Among 17 Patients from a Portuguese Tertiary Centre.

J Neuromuscul Dis. 2017

[4]
BMI and malignant hyperthermia pathogenic ryanodine receptor type 1 sequence variants in Switzerland: A retrospective cohort analysis.

Eur J Anaesthesiol. 2021-7-1

[5]
Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy.

Neuromuscul Disord. 2015-7

[6]
Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility.

Hum Mol Genet. 2022-11-28

[7]
Identification and Functional Analysis of RYR1 Variants in a Family with a Suspected Myopathy and Associated Malignant Hyperthermia.

J Neuromuscul Dis. 2020

[8]
Ryanodine receptor mutations in malignant hyperthermia and central core disease.

Hum Mutat. 2000

[9]
Next-generation sequencing and bioinformatics to identify genetic causes of malignant hyperthermia.

J Formos Med Assoc. 2021-2

[10]
Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database.

Eur J Hum Genet. 2021-12

引用本文的文献

[1]
Genetic Panel Testing for Malignant Hyperthermia in Japan: Discovery of Novel Variants and Clinical Implications.

Genes (Basel). 2025-8-11

[2]
Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy.

Sci Rep. 2023-9-5

[3]
Clinically actionable secondary findings in 130 triads from sub-Saharan African families with non-syndromic orofacial clefts.

Mol Genet Genomic Med. 2023-10

本文引用的文献

[1]
The GenomeAsia 100K Project enables genetic discoveries across Asia.

Nature. 2019-12-4

[2]
Large-Scale Whole-Genome Sequencing of Three Diverse Asian Populations in Singapore.

Cell. 2019-10-17

[3]
Genetic epidemiology of malignant hyperthermia in the UK.

Br J Anaesth. 2018-8-17

[4]
Ryanodine Receptor Structure and Function in Health and Disease.

Subcell Biochem. 2018

[5]
Malignant Hyperthermia and Ryanodine Receptor Type 1 Gene (RyR1) Mutation in a Family in Singapore.

Ann Acad Med Singap. 2017-12

[6]
Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept.

Anesthesiology. 2018-1

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Anesthesiology. 2018-1

[8]
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Am J Hum Genet. 2017-2-2

[9]
Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia.

Physiol Genomics. 2017-2-1

[10]
Analysis of protein-coding genetic variation in 60,706 humans.

Nature. 2016-8-18

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