Targeted Next-Generation Sequencing of the Leptin-Melanocortin Pathway in Severe Obesity

Pathogenic variants in five established leptin-melanocortin pathway genes (LEP, LEPR, MC4R, PCSK1, POMC) are associated with severe early-onset obesity and are targets for emerging treatments. However, these variants are rare in these patients, suggesting the involvement of additional genes interacting with this pathway.

Next-generation sequencing (NGS) analysis was performed in 395 patients with severe obesity, including 213 children (mean BMI: 56.3 kg/m²; BMI-z-score: 4.6). The analysis targeted 20 genes, including the 5 established genes. Rare genetic variants were assessed for pathogenicity using prediction algorithms, genetic databases, and literature review. Phenotypic data were retrospectively collected, focusing on obesity severity, age of onset, familial history, eating behavior disorder, neurodevelopmental and endocrine-associated diseases, and obesity complications.

Pathogenic heterozygous variants were identified in 34 patients (8.6%), 18 of them harboring pathogenic variants in the 15 additional genes. In adults, early-onset obesity was more frequent in potentially pathogenic variants carriers than in non-carriers (83.3% vs. 55.0%, p = 0.04). No differences were observed in the other phenotypic characteristics.

This supports the relevance of expanded genetic testing in severe obesity. Early-onset obesity remains a key clinical feature to guide genetic investigation and identify patients who may benefit from early personalized care and targeted treatments.