ESPE Abstracts

Background: The melanocortin-4 receptor (MC4R) pathway is critical for the regulation of energy balance. Variants in a number of genes within this pathway have well-established associations with severe obesity. However, the overall frequency of rare variants in these genes has not been assessed systematically in a clinically relevant population, and it is unknown whether variant frequency differs depending on the age of ascertainment. Genetic testing can improve diagnosis of rare genetic diseases of obesity and identify patients who may benefit from targeted therapeutic intervention.

Methods: We sequenced exons and intron-exon boundaries for 40 obesity-related genes in individuals with severe obesity (<18 years old, ³97^th percentile BMI for age; ³18 years old, BMI ³40kg/m²) who participated in the US-based Uncovering Rare Obesity™ diagnostic genetic testing program. This Next Generation Sequencing panel included 11 genes associated with non-syndromic obesity that encode proteins that function in the MC4R pathway (POMC, PCSK1, LEPR, SRC1, SH2B1, MC4R, MC3R, CPE, LEP, KSR2, and SIM1). Variants were classified as pathogenic/likely pathogenic (P/LP) or as a variant of uncertain significance (VUS) according to ACMG criteria. We additionally included one non-rare variant, PCSK1 p.N221D, for which published functional and population studies suggests a potential contribution to obesity. Patients with variants in 5 of these genes (POMC, PCSK1, LEPR, SRC1, and SH2B1) have previously been assessed in a trial using the MC4R agonist setmelanotide and demonstrated meaningful weight loss.

Results: Among the 7826 individuals, 16% were <6, 33% were 6 to 12, 30% were 12 to 18, and 21% were greater than 18 years old. 19% of individuals carried ≥1 rare variant in ≥1 of the 11 studied genes, including 3.6% carrying a P/LP variant and 15.4% carrying a VUS variant. Restricting to the 5 genes with prior demonstrated responsiveness to setmelanotide, the yield was 11% for P/LP or VUS variants. An additional 6.4% carried the PCSK1 p.N221D variant. No differences in yield were observed by age group.

Conclusions: In our large US-based cohort of individuals with severe early-onset obesity, 25.4% of individuals carry a potentially clinically relevant variant in one or more of 11 MC4R pathway-related genes. Genetic testing of patients with severe obesity may therefore be an important component of understanding the etiology of these patients’ phenotypes. No differences in yield were observed across age groups, indicating that genetic testing for obesity-related genes is appropriate in both pediatric and adult patients with severe obesity.