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

Abstract

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 amelanocyte stimulating hormone.Participants. Three hundred and twelve children (1-18 years, 50% girls) with body mass index (BMI) > 120% of 95 th 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.

The Families Improving Health Together (FIT) Program: Initial evaluation of retention and research in a multispecialty clinic for children with obesity

“…FIT collaborated with two NIH R01 grants (DK097399 and DK107735 studying FTO SNP's and feeding behavior and pediatric nonalcoholic hepatic steatosis respectively), one NIH K award (DK110539, studying obesity genetics), a grant from Regeneron, Inc. looking for specific genotypes and phenotypes for a clinical trial, and an internal grant examining the precursors and definition of metabolic syndrome in children. As reported in Section 3, research productivity was high with three nationally presented abstracts 42 , 43 , 44 with young investigators as primary authors, two manuscripts published 45 , 46 with FIT investigators as senior authors, and one manuscript in preparation. 47 The involvement of the entire team in discussing the care of each participant may have precipitated research by creating greater familiarity for all team members with the entire population and with different research protocols.…”

“…Research efforts were productive with successful establishment of the database integrated with the electronic medical record, three nationally presented abstracts 42 , 43 , 44 with young investigators as primary authors, two manuscripts published 45 , 46 with FIT investigators as senior authors, and one manuscript in preparation. 47 FIT collaborated with two NIH R01 grants (DK097399 and DK107735 studying FTO SNP's and feeding behavior and pediatric nonalcoholic hepatic steatosis respectively), one NIH K award (DK110539, studying obesity genetics), a grant from Regeneron, Inc. looking for specific genotypes and phenotypes for a clinical trial, and an internal grant examining the precursors and definition of metabolic syndrome in children.…”