Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort.
Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort.
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DOI：
10.1093/braincomms/fcad037
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发表时间：
2023
影响因子：
4.8
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中科院分区：
文献类型：
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我们研究的目的是在横截面患者中使用整个基因组测序，以鉴定与神经性疼痛有关的基因中的新变异，以确定已知的致病变异的普遍性，并了解致病变异和临床表现之间的关系。从英国的二级护理诊所招募了极端神经性疼痛表型（感官丧失和增益）的患者，并接受了整个基因组测序，作为美国国家健康与护理研究所生物库稀有疾病项目的一部分。一个多学科小组评估了以前已知引起神经性疼痛障碍的基因中稀有变异的致病性，并完成了研究候选基因的探索性分析。使用稀有变异的基因的关联测试使用联合负担和方差组件测试SKAT-O的基因方法完成。针对编码离子通道的基因的研究候选变异，对转染的HEK293T细胞进行了斑块夹分析。结果包括以下结果：（i）在12％的研究参与者（招募的205名）中发现了医学上可行的变体，包括已知的致病变异：SCN9A（ENST00000409672.1）：C.2544T> C，P.ILE848THR，导致遗传性红细胞生成等产生的ERYTHROMELLAMELGIA和SPTLC1（C.34025402554） p.cys133tr变体，导致遗传性感觉神经病类型1。 （ii）临床相关的变体在电压门控钠通道（NAV）中最常见。 （iii）SCN9A（ENST00000409672.1）：C.554G> a，PARG1855HIS变体在非冰冻冷损伤参与者中比对照组更为常见，并且在冷却后导致NAV1.7的功能获得（非释放冷损伤的环境触发）的功能）。 （iv）罕见的变体关联测试表明，基因，KIF1A，SCN8A，TRPM8，KIF1A，TRPA1以及具有神经病毒疼痛和对照的欧洲参与者之间的基因SCN11A，FLVCR1，KIF1A和SCN9A基因的调节区域的分布显着差异。 （v）TRPA1（ENST00000262209.4）：c.515c> t，p.Ala172Val变体，在具有情节性体细胞疼痛障碍的参与者中鉴定出来表明通道功能获得了激动剂刺激。整个基因组测序鉴定了超过10％的具有极端神经性疼痛表型的参与者的临床相关变体。这些变体中的大多数是在离子通道中发现的。将遗传分析与功能验证相结合可以使人们更好地理解离子通道中的罕见变体如何导致感觉神经元超过效果，以及作为环境触发的冷含量如何与功能获得的NAV1.7 P.Arg1855his变体相互作用。我们的发现突出了离子通道变体在极端神经性疼痛障碍发病机理中的作用，这可能是通过感觉神经元兴奋性的变化以及与环境触发因素的相互作用而介导的。
Themistocleous等。报告说，整个基因组测序揭示了12％患有极端神经性疼痛障碍的参与者的临床相关变体。大多数变体是在离子通道中的，包括新的表型关联（SCN9A P.ARG185HIS和非冻结冷损伤）和新型功能增益变体（TRPA1 P.Ala172Val和discododic Pain）。
The aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine the prevalence of known pathogenic variants and to understand the relationship between pathogenic variants and clinical presentation. Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK and underwent whole genome sequencing as part of the National Institute for Health and Care Research Bioresource Rare Diseases project. A multidisciplinary team assessed the pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels. The results include the following: (i) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: SCN9A(ENST00000409672.1): c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and SPTLC1(ENST00000262554.2):c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1. (ii) Clinically relevant variants were most common in voltage-gated sodium channels (Nav). (iii) SCN9A(ENST00000409672.1):c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls and causes a gain of function of NaV1.7 after cooling (the environmental trigger for non-freezing cold injury). (iv) Rare variant association testing showed a significant difference in distribution for genes NGF, KIF1A, SCN8A, TRPM8, KIF1A, TRPA1 and the regulatory regions of genes SCN11A, FLVCR1, KIF1A and SCN9A between European participants with neuropathic pain and controls. (v) The TRPA1(ENST00000262209.4):c.515C>T, p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain-of-channel function to agonist stimulation. Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to a better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain-of-function NaV1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers. Themistocleous et al. report that whole genome sequencing revealed clinically relevant variants in 12% of participants with extreme neuropathic pain disorders. The majority of variants were in ion channels, including new phenotype associations (SCN9A p.Arg185His and non-freezing cold injury) and novel gain-of-function variants (TRPA1 p.Ala172Val and episodic pain).
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影响因子：
7.4
作者：
Blesneac I;Themistocleous AC;Fratter C;Conrad LJ;Ramirez JD;Cox JJ;Tesfaye S;Shillo PR;Rice ASC;Tucker SJ;Bennett DLH
通讯作者：
Bennett DLH
影响因子：
7.4
作者：
Attal, Nadine;Lanteri-Minet, Michel;Bouhassira, Didier
通讯作者：
Bouhassira, Didier
影响因子：
14.5
作者：
Devigili, Grazia;Rinaldo, Sara;Lauria, Giuseppe
通讯作者：
Lauria, Giuseppe
影响因子：
5.3
作者：
Avenali, Luca;Narayanan, Pratibha;Schmidt, Manuela
通讯作者：
Schmidt, Manuela
影响因子：
11.2
作者：
Faber, Catharina G.;Hoeijmakers, Janneke G. J.;Merkies, Ingemar S. J.
通讯作者：
Merkies, Ingemar S. J.