Pain reports · 2026
Gene variants associated with pediatric-onset erythromelalgia: Mendelian and rare-variant association analyses.
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Yonas Matthew C, Ocay Don Daniel, Genetti Casie A, Lobo Kimberly, Fernandes Melissa, Groussis Nicole, Halpin Meghan, Wilder Robert T, Yu Timothy W, Berde Charles B, Brownstein Catherine A
Аннотация
INTRODUCTION: 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.
OBJECTIVES: The objective of this study was to uncover and assess gene variants potentially associated with pediatric-onset erythromelalgia.
METHODS: 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).
RESULTS: 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.
CONCLUSION: 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.
OBJECTIVES: The objective of this study was to uncover and assess gene variants potentially associated with pediatric-onset erythromelalgia.
METHODS: 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).
RESULTS: 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.
CONCLUSION: 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.