Peer-reviewed article
OR33-07 ARNT2: A Potential Novel Candidate Gene for Monogenic Obesity in Humans
Thaker V, Seaby E, Genetti C, Sutherland J, Ianello G et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a genetics research abstract reporting the discovery of potential mutations in the ARNT2 gene associated with early-onset severe obesity in two adolescent patients. The study uses whole exome sequencing and laboratory analysis to investigate how genetic variants affecting hypothalamic development might cause obesity. While the research involves children, it is a basic science and genetic discovery study rather than work focused on child well-being outcomes or interventions.
Key points
- Two adolescents with severe early-onset obesity were found to have rare variants in ARNT2, a gene critical for hypothalamic development
- Subject 1 developed severe obesity by age 2.5 years with BMI > 95th percentile, accompanied by developmental delay, seizures, and metabolic complications
- Subject 2 has biallelic variants in ARNT2 and early-onset obesity with bilateral focal epilepsy
- ARNT2 is a highly constrained gene with depletion of missense variants, suggesting mutations are functionally significant
- The authors propose hypomorphic mutations in ARNT2 as a potential cause of monogenic obesity in humans
Limitations
This is a case report of only two patients without a control group, and functional validation of the mutations is stated to be ongoing. The study does not evaluate any intervention or provide evidence on improving child health outcomes, instead focusing on genetic discovery.
Abstract
Abstract Introduction: Aryl hydrocarbon nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH)-PAS (Per/Arnt/Sim) transcription factor shown to be critical to the development of paraventricular nucleus of the hypothalamus (PVN), key region for energy homeostasis and feeding response. In vivo and in vitro studies have shown that ARNT2 is an obligate heterodimer for SIM1, known cause of monogenic obesity. Null mutations in Arnt2 in animals are not viable, but hypomorphic mutation results in hyperphagic obesity and its associated consequences (1). Due to the critical role of ARNT2 in the development of PVN, we hypothesize that hypomorphic mutations may result in early onset obesity in humans. Methods: The Genetics of Early Childhood Obesity (GECO) study recruits children with severe obesity (BMI > 120% of 95th percentile) of early onset (< 6 years). Whole exome sequencing (WES) was performed in a subset of proband-parent trios. The functional validation of the mutation(s) in ARNT2 is ongoing with co-transfection of tagged Arnt2 and Sim1 in HEK293 cells, with the induction of a luciferase reporter gene under the control of 6 repeats of bHLH-PAS core binding element by the Arnt2-Sim1 complex. Results: Two adolescents from unrelated families were found to have genetic variants in ARNT2. Subject 1 has a novel de novo heterozygous coding variant in ARNT2, c.388 C>G (p.P130A, CADD 25), predicted to be deleterious by 8/12 in silico algorithms. She is a 14-year old Caucasian girl with severe early onset obesity, BMI 28.1 kg/m2 (BMIz +4.72) at 2.5 years of age that has increased to 53.54 kg/m2 (BMIz + 3.25) at 14-years, and height > 95th %tile. She is non-dysmorphic, has developmental delay, absence seizures, behavior abnormalities & glucose intolerance/dyslipidemia secondary to obesity. Using genematcher, we identified another proband with the phenotype of obesity: an African American girl (BMIz +1.9) with biallelic inherited heterozygous variants in ARNT2, c.1228T>A (p.W410R, CADD 29) and c.916G>A (p.G306S, CADD 22). An only child conceived by IVF, she is non-dysmorphic and on treatment for bilateral focal epilepsy. All 3 variants are rare, with mean allele frequency < 0.005 in population-based databases such as gNOMAD. Both the patients have early onset obesity and a significant neurological phenotype. ARNT2 is a highly constrained gene of 717 amino acids with a significant depletion of missense variants in the N-terminus (1-244 aa) and overall fewer loss of function variants in ~282,644 alleles sequenced in gNOMAD. Conclusions: We propose that hypomorphic mutations in ARNT2 could be a potential novel cause of monogenic obesity in humans. Future studies will investigate the molecular mechanisms causing weight dysregulation in patient specific disease relevant hypothalamic neurons. Reference: (1) Turer et al., Dis Model Mech. 2018; 11(12)