TY - JOUR
T1 - Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity
AU - Loid, Petra
AU - Mustila, Taina
AU - Mäkitie, Riikka E.
AU - Viljakainen, Heli
AU - Kämpe, Anders
AU - Tossavainen, Päivi
AU - Lipsanen-Nyman, Marita
AU - Pekkinen, Minna
AU - Mäkitie, Outi
N1 - Funding Information:
We thank all the patients and their family members for participating in the study. We thank RN P?ivi Turunen for help with data collection. Funding. This study was financially supported by the Academy of Finland; Sigrid Jus?lius Foundation; Foundation for Pediatric Research; Folkh?lsan Research Foundation; P?ivikki ja Sakari Sohlberg Foundation; Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkl?ns minne; Emil Aaltonen Foundation; Swedish Research Council; Novo Nordisk Foundation; University of Helsinki through the Doctoral Program in Clinical Research; Helsinki University Hospital research funds.
Publisher Copyright:
© Copyright © 2020 Loid, Mustila, Mäkitie, Viljakainen, Kämpe, Tossavainen, Lipsanen-Nyman, Pekkinen and Mäkitie.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2/21
Y1 - 2020/2/21
N2 - 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 patient), possibly contributing to the obesity phenotype in these patients. Altogether 8 % (7/92) of the subjects had rare pathogenic/likely pathogenic variants in the studied genes. Conclusions: Rare genetic variants within the hypothalamic circuit are prevalent and contribute to the development of severe early-onset obesity. Targeted exome sequencing is useful in identifying affected subjects. Further studies are needed to evaluate the variants' clinical significance and to define optimal treatment.
AB - 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 patient), possibly contributing to the obesity phenotype in these patients. Altogether 8 % (7/92) of the subjects had rare pathogenic/likely pathogenic variants in the studied genes. Conclusions: Rare genetic variants within the hypothalamic circuit are prevalent and contribute to the development of severe early-onset obesity. Targeted exome sequencing is useful in identifying affected subjects. Further studies are needed to evaluate the variants' clinical significance and to define optimal treatment.
KW - appetite regulation
KW - childhood obesity
KW - hyperphagia
KW - hypothalamus
KW - MC4R
U2 - 10.3389/fendo.2020.00081
DO - 10.3389/fendo.2020.00081
M3 - Article
AN - SCOPUS:85081678883
SN - 1664-2392
VL - 11
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
M1 - 81
ER -