Genotype–Phenotype Spectrum of Non‐Syndromic Monogenic Obesity in a National Paediatric Cohort
Authors' conclusion
Biallelic LEPR, particularly those with double homozygous missense variants, and MC4R variants represent the most metabolically adverse forms of monogenic obesity, extending current evidence beyond BMI-based risk stratification. In LEPR, advanced bone age may contribute to impaired growth. These data provide a comprehensive genotype-phenotype characterisation in a genetically homogeneous population and emphasise the importance of early diagnosis for risk stratification.
Study context
- Population
- Children with non-syndromic monogenic obesity (leptin-melanocortin pathway variants), 23 paediatric endocrinology centres, Türkiye; 49% female, median age 10.0 years
- Participants
- 130 children
- Exposure
- Genotype–phenotype comparison across monogenic obesity subtypes
- Biallelic LEPRn = 47
- Monoallelic MC4Rn = 49
- POMCn = 13
- Biallelic MC4Rn = 11
- Outcome
- BMI-SDS and metabolic profile (SPISE index) by genotype
Methodological detailsmulticentre, Data collected using a standardised case record form
- Multicentre
- Data collected using a standardised case record form
Main finding
As reported in the abstract
- Higher BMI-SDS with LEP, LEPR and biallelic MC4R than POMC and monoallelic MC4R
- p < 0.0001
- SPISE index differed across groups; lower in biallelic LEPR and MC4R vs monoallelic MC4R
- p = 0.0051
- Within LEPR, 'double homozygous' missense variants: poorer metabolic outcomes independent of BMI-SDS
- p < 0.05
Observational data: associations, not effects.
Further findings
Bone age and growth
- Bone age advanced in LEPR vs POMC, biallelic and monoallelic MC4R
- P = 0.013
- Bone age-adjusted height-SDS lower than non-adjusted height-SDS
- P = 0.004
Original publication
Genotype–Phenotype Spectrum of Non‐Syndromic Monogenic Obesity in a National Paediatric Cohort. Pediatr Obes. Published 28 May 2026. doi:10.
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