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J Clin Endocrinol Metab. 2019 Jul 1;104(7):2961-2970. doi: 10.1210/jc.2018-02657.

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

Author information

1
Division of Molecular Genetics, Columbia University Medical Center, New York, New York.
2
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
3
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
4
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
5
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
6
School of Medicine, Boston University School of Medicine, Boston, Massachusetts.
7
Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, Massachusetts.
8
Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, New York.
9
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
10
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
11
Columbia Stem Cell Initiative, Columbia University Medical Center, New York, New York.
12
Center for Basic and Translational Obesity Research and Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts.
13
Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, Massachusetts.
14
Departments of Pediatrics and Genetics, Harvard Medical School, Boston, Massachusetts.

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.

PMID:
30811542
PMCID:
PMC6546308
[Available on 2020-02-27]
DOI:
10.1210/jc.2018-02657

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