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

Petra Loid, Taina Mustila, Riikka E. Mäkitie, Heli Viljakainen, Anders Kämpe, Päivi Tossavainen, Marita Lipsanen-Nyman, Minna Pekkinen, Outi Mäkitie

Research output: Contribution to journalArticleScientificpeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Article number81
JournalFrontiers in Endocrinology
Publication statusPublished - 21 Feb 2020
Publication typeA1 Journal article-refereed


  • appetite regulation
  • childhood obesity
  • hyperphagia
  • hypothalamus
  • MC4R

Publication forum classification

  • Publication forum level 1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism


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