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Clinical and Functional Characterization of Melanocortin 4 Receptor genetic variants in African American and/or Hispanic children with severe early onset obesity

Context Mutations in melanocortin receptor (MC4R) are the most frequent cause of monogenic obesity in children of European ancestry, but little is known about their prevalence in children from minority populations in the United States. Objective This study aims to identify the prevalence of MC4R mutations in children with severe early onset obesity of African-American and/or Latina ancestry. Design and Setting Individuals were recruited from the weight management clinics at two hospitals and from the institutional biobank at a third hospital. Sequencing of the MC4R gene was performed by whole exome and/or Sanger sequencing. Functional testing was performed to establish the surface expression of the receptor and cAMP response to its cognate ligand α-melanocyte stimulating hormone. Participants Three hundred and twelve children (1-18 years, 50% girls) with body mass index (BMI) > 120% of 95th percentile of CDC 2000 growth charts at an age < 6 years, with no known pathological cause of obesity were enrolled. Results Eight rare MC4R mutations (2.6%) were identified in this study (R7S, F202L (n=2), M215I, G252D, V253I, I269N, F284I), three of which have not been previously reported (M215I, G252D, F284I). The pathogenicity of the variants was confirmed either by prior literature reports, or by functional testing. There was no significant difference in the BMI or height trajectories of children with or without MC4R mutations in this cohort. Conclusions While the prevalence of MC4R mutations in this cohort was similar to that reported in obese children of European ancestry, some of the variants were novel.