# A Novel Maternally Inherited GNAS Variant in a Family With Hyperphagia and Obesity: 3 Cases

## TL;DR

A new GNAS gene variant is found in a family with obesity and hyperphagia, showing how genetic changes can cause varied symptoms.

## Contribution

A novel GNAS missense variant is identified and functionally characterized in a family with obesity and hyperphagia.

## Key findings

- The GNAS variant c.791A > C, p.(Asp264Thr) impairs cAMP production through multiple receptors.
- The variant was found in three family members with obesity, hyperphagia, and mild developmental delays.
- This case highlights the clinical heterogeneity of monogenic obesity and the need for broader genetic testing.

## Abstract

GNAS variants were recently described in 1% of patients not known to have pseudohypoparathyroidism/inactivating PTH/PTHrP signalling disorder 2 in the UK Genetics of Obesity Study. We describe a new missense GNAS variant, c.791A > C, p.(Asp264Thr), in a family with obesity, hyperphagia and mild PTH resistance. A 6-year-old female (body mass index +4.3 SD score [SDS], height +1.9 SDS) presented with hyperphagia and obesity from age 3 years. She had subtle brachydactyly, macrocephaly, and mildly delayed development. The 12-year-old brother (height +2.1 SDS, body mass index +2.9 SDS) had hyperphagia, obesity, mildly delayed development, and autism. He had subtle brachydactyly, as did the affected mother. We assessed the functional effect of the mutant, measuring cAMP production in cells transfected with wild type and mutant GNAS after ligand stimulation. Cells with the mutant GNAS showed impaired cAMP generation through melanocortin receptor 4, GH releasing hormone receptor, and PTH receptor. These cases demonstrate the clinical heterogeneity of monogenic disease, suggesting a need to test for PHP1A in children with obesity even without classical signs of PHP1A.