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

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.

Keywords: MC4R; appetite regulation; childhood obesity; hyperphagia; hypothalamus.

Figure 1

Schematic presentation of the genes included in the panel.

Figure 2

Chromatograms of Sanger sequence analysis of MC4R showing a heterozygous frameshift deletion (p.V103Afs5*) in two index patients with monogenic obesity (A) and the normal MC4R sequence (B).

Figure 3

Schematic presentation of the MC4R protein and the location of the frameshift variant (p.V103Afs5*) and the missense variant (p.T112M) identified in patients with obesity.

Figure 4

Pedigrees of the families with MC4R frameshift variant (p.V103Afs5*). Square = male, circle = female, +/– heterozygote carrier, –/– wildtype. Black square/circle = obesity, gray square/circle = overweight, white square/circle = normal weight.