Journal Article

Characterization of Rare Variants in MC4R in African American and Latino Children With Severe Early-Onset Obesity

Liimatta, Kalle, Chesi, Alessandra, Hirschhorn, Joel N, Hakonarson, Hakon, De Rosa, Maria Caterina, McDonald, Molly, McCormack, Shana, Thaker, Vidhu V, Christensen, Sinead, Grant, Struan F A, Weaver, Benjamin, Zhou, Justin, Rosenbaum, Michael, Doege, Claudia A

2019

Overview

Abstract Context Mutations in melanocortin receptor (MC4R) are the most common cause of monogenic obesity in children of European ancestry, but little is known about their prevalence in children from the 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 or Latino ancestry. Design and Setting Participants 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 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 twelve children (1 to 18 years old, 50% girls) with body mass index (BMI) >120% of 95th percentile of Centers for Disease Control and Prevention 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, and F284I], three of which were not previously reported (G252D, F284I, and R7S). The pathogenicity of selected variants was confirmed by prior literature reports or functional testing. There was no significant difference in the BMI or height trajectories of children with or without MC4R mutations in this cohort. Conclusions Although the prevalence of MC4R mutations in this cohort was similar to that reported for obese children of European ancestry, some of the variants were novel. This study identifies pathogenic variants in the MC4R gene in children with severe early-onset obesity from African American race and Latino ancestry.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Age / Body height / Body mass index / Children / Clinical s / Cyclic adenylic acid / DNA sequencing / Health aspects / Hispanic Americans / Hospitals / Massachusetts / Melanocortin / Melanocortin MC4 receptors / Mutation / New York / Nucleotide sequencing / Obesity / Obesity in children / Pathogenicity / Pennsylvania / Weight control