ESPE Abstracts

Introduction: Monogenic obesity is characterised by early-onset, severe obesity ((body mass index) BMI >99.6^th centile) and hyperphagia. Access to genetic testing is limited, thus prevalence may be underestimated. Genes in the leptin-melanocortin pathway, related to the hypothalamic control of food intake, are frequently involved. We report results obtained via the Rare Obesity Advanced Diagnosis^TM genetic testing program.

Methods: 93 patients with severe obesity ((body mass index) BMI >99.6^th centile for age) under the care of a tertiary paediatric weight management service were screened using a targeted obesity-related gene panel. Blood, saliva or buccal samples were taken. The 79-gene panel included genes encoding proteins in the leptin-melanocortin pathway and assessment for rearrangement of the 16p11.2 chromosomal region. Variants were classified as pathogenic or potentially relevant variants; further subdivided into suspected pathogenic, variants of unknown significance and suspected benign.

Results: 54/93 patients were female. Age ranged from 1.5-17.5 years and median age-of-onset of obesity was 3 years (range 1-11). Median BMI at testing was 32.6 kg/m² (range 22.4-55.0) and median BMI SDS was 3.9 (range 2.1-6.0). Pathogenic variants were found in 11.8% patients (11/93), suspected pathogenic in 7.5% (7/93), variants of unknown significance in 14.0% (13/93), suspected benign in 17.2% (16/93) and one had a deletion in the 16p11.2 region. MC4R heterozygous was the most frequently identified pathogenic variant, representing 5.4% (5/93) of the samples. PCSK1 p.(Asn221Asp), a variant conferring polygenic risk for obesity, was found in 12.9% (12/93) of patients.

Conclusions: In our cohort, a pathogenic variant was identified in over 1/10 patients and suspected pathogenic variants in a further 1/20 patients. Most variants identified involved genes in the MC4R-pathway. Targeted therapies for MC4R variants, such as setmelanotide, are emerging as promising treatment options. Wider availability of testing may enable a better understanding of obesity genetics and the development of further precision, personalised therapies.