Investigating genotype–phenotype relationship of extreme neuropathic pain disorders in a UK national cohort. Issue 2 (20th February 2023)

• Record Type: Journal Article
• Authors: Themistocleous, Andreas C; Baskozos, Georgios; Blesneac, Iulia; Comini, Maddalena; Megy, Karyn; Chong, Sam; Deevi, Sri V V; Ginsberg, Lionel; Gosal, David; Hadden, Robert D M; Horvath, Rita; Mahdi-Rogers, Mohamed; Manzur, Adnan; Mapeta, Rutendo; Marshall, Andrew; Matthews, Emma; McCarthy, Mark I; Reilly, Mary M; Renton, Tara; Rice, Andrew S C; Vale, Tom A; van Zuydam, Natalie; Walker, Suellen M; Woods, Christopher Geoffrey; Bennett, David L H
• Is Part Of: Brain communications. Volume 5:Issue 2(2023)
• Publication Date: 2023-02-20
• Subjects: neuropathic pain -- whole genome sequencing -- peripheral neuropathy -- sodium channels; 616
• DOI: 10.1093/braincomms/fcad037
• Languages: English
• ISSNs: 2632-1297

Abstract

Abstract: 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 NaV 1.7 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 NaV 1.7 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. Abstract : 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). Graphical Abstract: Graphical abstract