Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity.

Frontiers in Endocrinology
Petra LoidOuti Mäkitie

Abstract

Context: The hypothalamic circuit has an essential role in the regulation of appetite and energy expenditure. Pathogenic variants in genes involved in the hypothalamic leptin-melanocortin pathway, including melanocortin-4-receptor (MC4R), have been associated with monogenic obesity. Objective: To determine the rate and spectrum of rare variants in genes involved in melanocortin pathway or hypothalamic development in patients with severe early-onset obesity (height-adjusted weight >60% before age 10 years). Methods: We used a custom-made targeted exome sequencing panel to assess peripheral blood DNA samples for rare (minor allele frequency <0.5%), pathogenic/likely pathogenic variants in 24 genes related to the hypothalamic circuit in 92 subjects (51% males, median age 13.7 years) with early-onset severe obesity (median body mass index (BMI) Z-score + 4.0). Results: We identified a novel frameshift deletion in MC4R (p.V103Afs5*) in two unrelated patients and a previously reported MC4R variant (p.T112M) in one patient. In addition, we identified rare heterozygous missense variants in ADCY3 (p.G1110R), MYT1L (p.R807Q), ISL1 (p.I347F), LRP2 (p.R2479I, and p.N3315S) and a hemizygous missense variant in GRPR (p.L87M) (each in one pat...Continue Reading

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Citations

Feb 25, 2021·Obesity Research & Clinical Practice·Laura M L CarvalhoCarla Rosenberg
Apr 17, 2021·Neuropharmacology·Katherine M SerafineEric P Zorrilla

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Methods Mentioned

BETA
exome sequencing
PCR

Software Mentioned

Ensembl Variant Effector Predictor ( VEP
Platypus
SPSS
Primer3
VarAFT

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