ESPE Abstracts

Genetic obesity is rare and usually affects the hunger/satiety circuit. Monogenic obesity is mainly due to variants in genes of the leptin-melanocortin pathway which regulates the control of food intake. Melanocortin 4 receptor (MC4R)-linked obesity has been reported as one of the most common forms of monogenic obesity. Mutations in the MC4R gene have been described in 2-3% of obese children and adults with variable severity of obesity and no additional phenotype. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. During the last decades, next-generation sequencing techniques have improved the diagnostic ability in diagnosis genetic obesity and identifying new genetic variants involved in this complex phenotype. The objective is to evaluate the frequency of gene variants in a local population of children with severe early-onset obesity.

Methods: children with severe early-onset obesity were screened for genetic obesity according to the Rare Obesity Advanced Diagnosis™ (ROAD) genetic testing. Variants were classified as pathogenic/likely pathogenic/variants of unknown significance (P/LP/VUS) according to American College of Medical Genetics criteria. The VUS category was further divided into suspected pathogenic (SP), uncertain, or suspected benign (SB) based on available evidence.

Results: 347 children and adolescents (51.7% females) with a mean age of 10.2± 3.3 years, and mean z-score BMI of 3.45±1.07 were tested. Among the subjects genotyped, 40% showed no genetic variants. Overall, 5% of variants were P, 13% LP, 3% SP, and 79% VUS. The VUS category included 53% uncertain, 23% SP, and 24% SB. The pathway of plexins-semaphorins was the most frequently mutated (n = 64, 18.4%). Among the individuals tested, 2.3% carried a genetic variant in the SH2B1 gene (2 deletions of 16p11.2; 2 P, 1 SP, 2 SB, and 5 VUS), and 0.1% in the MC4R gene (4 LP and 1 VUS). Subjects carriers of SH2B1 deficiency showed a heterogeneous phenotype for hyperphagia and neuropsychological comorbidities. Biallelic mutations in ALMS1 were found in 0.1% and biallelic mutations in genes involved in Bardet Biedel Syndrome were observed in 1.08%.

Conclusion: SH2B1 deficiency is the most common genetic cause of obesity in this cohort of children with early-onset obesity with different clinical presentations. Mutations in MC4R were rare. At diagnosis, not all patients had a clear clinical phenotype. This indicates that genetic testing for 16p11.2 deletion should be included in panels for early-onset obesity, not just those investigating suspected syndromic disease.