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 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.
Highlights
Obesity is a complex disease with various contributing environmental and genetic factors
We found rare pathogenic/likely pathogenic variants in 7/92 (8%) of the study subjects and one rare variant of uncertain significance in one patient
We identified a heterozygous missense variant in ADCY3 (c.3328G>C, p.G1110R) in Patient 4; a 16-year-old female with a body mass index (BMI) Z-score of +4.8, insulin resistance, asthma and depression
Summary
Obesity is a complex disease with various contributing environmental and genetic factors. To uncover the principal genetic factors behind obesity, several advanced research strategies have been used, including twin studies, genome-wide association studies (GWASs), chromosomal microarray analyses and generation sequencing [1]. We and others have shown that rare copy number variants (CNVs) are enriched in patients with early-onset severe obesity [4,5,6]. It has been suggested that obesity could be a consequence of rare genetic variants with strong effect [7, 8]. Despite these advancements, the genetic causes and underlying molecular mechanisms behind obesity are still inadequately understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
