Mutations in the alpha subunit of voltage-gated sodium channel 1.7 (Na V 1.7), encoded by SCN9A gene, play an important role in the regulation of nociception, and can lead to a wide range of clinical outcomes, ranging from extreme pain syndromes to congenital inability to experience pain.To expand the phenotypic and genotypic spectrum of SCN9A-related channelopathies we describe the proband, a daughter born from consanguineous parents, that had pain insensitivity, diminished temperature sensation, foot burns, and severe loss of nociceptive nerve fibers in the epidermis.Next-generation sequencing of SCN9A (NM_002977.3) revealed a novel homozygous substitution (c.377+7T>G) in the donor splice-site of intron 3. As the RNA functional testing is challenging, the in silico analysis are the first approach to predict possible alterations. In this case, the computational analysis was unable to identify the splicing consensus and couldn't provide any prediction for splicing defects. The affected intron indeed belongs to the U12-type, a family of introns characterised by non-canonical consensus at splice-sites, accounting only for 0.35% of all human introns, and are not included in most of the training-sets for splicing prediction. Functional study on proband RNA shown different aberrant transcripts, where exon 3 was missing and an intron fragment was included. Quantification study using real-time PCR showed a significant reduction of the Na V 1.7 canonical transcript. Collectively, these data widen the spectrum of SCN9A-related insensitivity to pain, by describing a mutation causing Na V 1.7 deficiency, underlying the nociceptor A C C E P T E D 8 8 3 dysfunction, and highlights the importance of molecular investigation of U12-introns mutations despite the silent prediction.
Missing aspects of the heritability of chronic neuropathic pain, as a complex adult-onset trait, may be hidden within rare variants with low effect on disease risk, unlikely to be resolved by a single-variant approach. To identify new risk genes, we performed a next-generation sequencing of 107 pain genes and collapsed the rare variants through gene-wise aggregation analysis. The optimal unified sequence kernel association test was applied to 169 patients with painful neuropathy, 223 patients with nociplastic pain (82 diagnosed with chronic widespread pain and 141 with fibromyalgia), and 216 healthy controls. Frequency and features of variants in TRPA1, which was the most significant gene, were further validated in 2 independent cohorts of 140 patients with chronic pain (90 with painful neuropathy and 50 with chronic widespread pain) and 34 with painless neuropathy. The effect of aminoacidic changes were modeled in silico according to physicochemical characteristics. TRPA1 was significantly enriched of rare variants which significantly discriminated chronic pain patients from healthy controls after Bonferroni correction (P = 6.7 × 10−4, ρ = 1), giving a risk of 4.8-fold higher based on the simple burden test (P = 0.0015, OR = 4.8). Among the 32 patients harboring TRPA1 variants, 24 (75%) were diagnosed with nociplastic pain, either fibromyalgia (12; 37.5%) or chronic widespread pain (12; 37.5%), whereas 8 (25%) with painful neuropathy. Irrespective of the clinical diagnosis, 12 patients (38%) complained of itch and 10 (31.3%) of cold-induced or cold-accentuated pain, mostly episodic. Our study widens the spectrum of channelopathy-related chronic pain disorders and contributes to bridging the gap between phenotype and targeted therapies based on patients' molecular profile.
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