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 SCN9A, encoding voltage-gated sodium channel NaV1.7. However, approximately 65% to 85% of patients with erythromelalgia do not have pathogenic SCN9A 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 (PRDM12) and dihydropyrimidinase-like protein 2 (DPYSL2). In a targeted 12-gene rare-variant set analysis using SKAT-O, zinc finger homeobox protein 2 (ZFHX2) showed evidence of association (P = 6.9 × 10^-4), surpassing Bonferroni correction for 12 tests (α = 4.17 × 10^-3), whereas KIF1B showed only a nominal association signal (P = 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 PRDM12 and DPYSL2 were identified in a pediatric erythromelalgia cohort and a gene-based rare-variant association signal for ZFHX2 was identified, replication and functional validation are needed.