Genotype-Phenotype Spectrum of Non-Syndromic Monogenic Obesity in a National Paediatric Cohort

Non-syndromic monogenic obesity, caused by defects in the leptin-melanocortin pathway, presents with early-onset severe obesity and hyperphagia, but genotype-phenotype and metabolic correlations across different genetic forms remain unclear.

In this multicentre retrospective cohort study, individuals with biallelic (likely) pathogenic variants in LEP, LEPR, POMC, PCSK1, MC4R, ADCY3, and monoallelic (likely) pathogenic MC4R variants were recruited from 23 paediatric endocrinology centres across Türkiye. Anthropometric, clinical, metabolic data, including HOMA-IR and SPISE index, systematically applied across different monogenic obesity subtypes, were collected using a standardised case record form.

A total of 130 individuals (49% female; median age 10.0 years) were included. Biallelic LEPR (n = 47) and monoallelic MC4R (n = 49) variants were the most frequent causes, followed by biallelic POMC (n = 13) and MC4R (n = 11) variants. Individuals with LEP, LEPR, and biallelic MC4R variants had higher BMI-SDS than those with POMC and monoallelic MC4R variants (p < 0.0001). SPISE index differed across groups (p = 0.0051), with lower values in biallelic LEPR and MC4R compared with monoallelic MC4R variants. Within LEPR, individuals carrying 'double homozygous' missense variants showed poorer metabolic outcomes independent of BMI-SDS (p < 0.05). POMC deficiency showed a similar phenotype to monoallelic MC4R, with later obesity onset, lower BMI-SDS, and a more favourable metabolic profile. Bone age was advanced in LEPR compared to POMC, biallelic and monoallelic MC4R variants (p = 0.013) and bone age-adjusted height-SDS was lower than non-adjusted height-SDS (p = 0.004), indicating impaired growth when adjusted for skeletal maturation.

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.