Endocrine Abstracts

Introduction: A proportion of severe obesity is due to monogenic inheritance, however access to genetic testing is often limited which may underestimate prevalence. We report our data obtained via the Rare Obesity Advanced Diagnosis™ genetic testing program established to diagnose rare genetic causes of obesity.

Methods: 49 patients (22 male) under the care of a tier 3 paediatric weight management service with early-onset (<5 years of age) severe obesity (BMI ≥99.6th centile-for-age) and hyperphagia were screened for monogenic obesity variants using a targeted gene panel, consisting of 79 obesity related genes. The panel also included the genes encoding proteins in the leptin–melanocortin pathway (POMC, PCSK1, LEPR, NCOA1, SH2B1, MC4R, MC3R, CPE, LEP, KSR2, SIM1) and assessment of rearrangement of the 16p11.2 chromosomal region. Variants were classified as pathogenic or potentially relevant which was subdivided into suspected pathogenic (SP), variant of unknown significance (VUS), or suspected benign (SB) utilising available evidence.

Results: Patients ranged from 1.5 to 17.5 years, mean BMI–SDS was 4.0(range 2.1–6.0) and mean reported age-of-onset of obesity was 3.3 years(range 1–9). Pathogenic variants were identified in 10.2%(5/49), SP in 10.2%(5/49), VUS in 22.4%(11/49) and SB in 10.2%(5/49) of patients and one had a deletion in 16p11.2 region. PCSKI p.(Asn221Asp), a variant conferring polygenic risk for obesity, was found in 12.2%(6/49) patients.

Conclusions: In our cohort, variants involving genes in the MC4R pathway were the most frequent, representing 8.1% of pathogenic and 14.2% of potentially relevant variants. With the emergence of targeted therapies, for example the MC4R agonist setmelanotide for certain MC4R pathway variants, genetic testing for severe obesity may facilitate a deeper understanding of aetiology and enable targeted treatment.