Gene variants associated with pediatric-onset erythromelalgia: Mendelian and rare-variant association analyses.
Erythromelalgia is a descriptive term for burning pain and erythema in distal extremities, often worsened by heat and improved by cold. Inherited erythromelalgia has been primarily linked to gain-of-function variants in , encoding voltage-gated sodium channel NaV1.7. However, approximately 65% to 85% of patients with erythromelalgia do not have pathogenic variants. The objective of this study was to uncover and assess gene variants potentially associated with pediatric-onset erythromelalgia. With IRB approval and informed consent, probands and families with erythromelalgia underwent next-generation sequencing. A list of genes of interest was produced based on Mendelian inheritance models. Selected gene candidates were assessed using the Sequence Kernel Association Test-Optimal (SKAT-O). Sixty-two probands with erythromelalgia and their relatives were included in Mendelian analysis, which identified variants in PR domain zinc finger protein 12 () and dihydropyrimidinase-like protein 2 (). In a targeted 12-gene rare-variant set analysis using SKAT-O, zinc finger homeobox protein 2 () showed evidence of association ( = 6.9 × 10), surpassing Bonferroni correction for 12 tests (α = 4.17 × 10), whereas showed only a nominal association signal ( = 0.03) that did not survive multiple-testing correction. Genes associated with both increased and decreased pain sensitivity are of considerable interest for elucidating pain mechanisms and analgesic development. As rare variants in and were identified in a pediatric erythromelalgia cohort and a gene-based rare-variant association signal for was identified, replication and functional validation are needed.