Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Background: The melanocortin 4 receptor (MC4R) pathway is critical for the regulation of energy balance. Variants within genes comprising this pathway, including POMC, PCSK1, LEPR, SH2B1, and SRC1, have a well-established association with severe obesity. However, the frequency of variants in these genes have not been assessed systematically in a clinically relevant US population. Methods: We sequenced POMC, PCSK1, LEPR, SH2B1, and SRC1 exons and intron-exon boundaries in 35,276 US individuals with severe obesity (<18 years old, >97th percentile BMI for age; >18 years old, BMI >40kg/m2). This cohort is comprised of individuals sequenced across multiple initiatives, including the Uncovering Rare Obesity (URO) diagnostic genetic testing program. In the current analysis, we included rare variants 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, which for which published functional and population studies suggests a potential contribution to obesity. Results: 10.2% of individuals with severe obesity carried >1 rare variants in >1 of the 5 studied genes, including 0.7% who carry a P/ LP variant and 9.5% who carry a VUS variant. An additional 5.4% carried the PCSK1 p.N221D variant. Within the context of a community focused clinical diagnostic tool, URO demonstrated a slightly higher frequency of P/LP and PCSK1 N221D genotypes, 1.2% and 6.9%, respectively, and a 9.8% frequency of VUS genotypes. Conclusions: Overall, in our large US-based cohort of individuals with severe early-onset obesity, 15.6% of individuals carry a potentially clinically relevant variant in the MC4R pathway genes POMC, PCSK1, LEPR, SH2B1, and SRC1. Understanding the role of these variants in the pathophysiology of obesity may improve the clinical care of individuals living with these rare genetic diseases of obesity.