EP126: Frequency of MC4R pathway variants in a large US cohort of pediatric and adult patients with severe obesity

Abstract

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. We sequenced exons and intron-exon boundaries for 40 obesity-related genes in individuals with severe obesity (defined as ≥97th percentile of body mass index [BMI] for age in those <18 years old, or BMI ≥40 kg/m2 in those ≥18 years old) who participated in the US-based Uncovering Rare Obesity diagnostic genetic testing program. This next-generation sequencing panel included 11 genes associated with nonsyndromic obesity that encode proteins functioning in the MC4R pathway (POMC, PCSK1, LEPR, SRC1 [NCOA1], 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 American College of Medical Genetics and Genomics criteria. We additionally included 1 nonrare variant, PCSK1 p.N221D, for which published functional and population studies suggests a potential contribution to obesity. Individuals 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. Variants were classified according to their classical mode of inheritance (autosomal dominant: SRC1, SH2B1, MC4R, MC3R, KRS2, and SIM1; autosomal recessive: POMC, PCSK1, CPE, and LEP). Among 7,826 individuals, 16%, 33%, 30%, and 21% were aged <6, 6–12, 12–18, and >18 years, respectively. Among these individuals, 19% 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. Additionally, 11.9% of individuals had variants in line with mode of inheritance, including 2.1% of individuals with all P/LP variants. Restricting to the 5 genes with prior demonstrated responsiveness to setmelanotide (POMC, PCSK1, LEPR, SRC1, and SH2B1), the variant frequency was 11% for P/LP or VUS variants. An additional 6.4% of individuals carried the PCSK1 p.N221D variant. No differences in frequency were observed by age group. In our large US-based cohort of individuals with early-onset, severe obesity, 25.4% of individuals carried a potentially clinically relevant variant in ≥1 of 11 MC4R pathway–related genes, including 11.9% of individuals with variants in line with classical mode of inheritance. Genetic testing of patients with severe obesity may therefore be an important component of understanding the etiology of these patients’ phenotypes. No differences in variant frequency were observed across age groups, indicating that genetic testing for obesity-related genes is appropriate in both pediatric and adult patients with severe obesity.