Abstract
Purpose
Recessive deficiency of proopiomelanocortin (POMC) causes childhood-onset severe obesity.
Cases can now benefit from the melanocortin 4 receptor agonist setmelanotide. Furthermore,
a phase 3 clinical trial is evaluating setmelanotide in heterozygotes for POMC. We performed a large-scale genetic analysis to assess the effect of heterozygous,
pathogenic POMC variants on obesity.
Methods
A genetic analysis was performed in a family including 2 cousins with childhood-onset
obesity. We analyzed the obesity status of heterozygotes for pathogenic POMC variants in the Human Gene Mutation Database. The association between heterozygous
pathogenic POMC variants and obesity risk was assessed using 190,000 exome samples from UK Biobank.
Results
The 2 cousins carried a compound heterozygous pathogenic variant in POMC. Six siblings were heterozygotes; only 1 of them had obesity. In Human Gene Mutation
Database, we identified 60 heterozygotes for pathogenic POMC variants, of whom 14 had obesity. In UK Biobank, heterozygous pathogenic POMC variants were not associated with obesity risk, but they modestly increased body
mass index levels.
Conclusion
Heterozygous pathogenic POMC variants do not contribute to monogenic obesity, but they slightly increase body
mass index. Setmelanotide use in patients with obesity, which would only be based
on the presence of a heterozygous POMC variant, can be questioned.
Keywords
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Article info
Publication history
Published online: April 20, 2023
Accepted:
April 16,
2023
Received in revised form:
April 15,
2023
Received:
December 9,
2022
Identification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
