Genetic burden of rare leptin-melanocortin variants in pediatric nonsyndromic obesity: Evidence from a Taiwanese cohort.

BACKGROUND

Rare and deleterious variants in the leptin-melanocortin pathway can underlie severe childhood obesity, but data from East Asian populations remain limited.

METHODS

We conducted a single-center prospective observational cohort study of 188 Taiwanese children (4-18 years) with nonsyndromic obesity recruited between Jan 2017 and Dec 2024 for targeted sequencing of 12 leptin-melanocortin genes and compared them with two cohorts from the Taiwan Biobank: 527 normal‑weight adults presumed to have normal weight in childhood and 213 obese adults. We compared carrier proportions and mean variant counts and applied the Optimal Sequence Kernel Association Test (SKAT-O) across groups at the pathway and gene levels for three variant sets: all exonic variants, rare variants, and potentially influential variants (PIVs, defined as rare protein-truncating variants or missense variants with high deleteriousness scores). We also analyzed questionnaire-derived eating behavior scores using SKAT-O within the childhood obesity cohort.

RESULTS

Children with obesity carried a higher PIV burden than both normal-weight adults (41.0% vs. 24.1%; p < 0.0001) and obese adults (41.0% vs. 25.8%; p = 0.001); mean PIV counts were also higher. Pathway-level SKAT-O supported enrichment driven by rare variants and PIVs. Gene-level enrichment for LEPR and MAGEL2, and variant-level enrichment for two missense variants, MAGEL2 p.Gly285Arg and LEPR p.Asn128Lys, were observed in the childhood obesity group. Analyses of eating‑behavior scores showed nominal signals for exonic variants in MAGEL2 and PIVs in SIM1, but neither met the Bonferroni‑corrected threshold.

CONCLUSIONS

Rare, putatively deleterious leptin-melanocortin variants, particularly in LEPR and MAGEL2, are enriched in Taiwanese children with nonsyndromic obesity, underscoring the value of pathway-focused genetic evaluation in pediatric obesity.