de Oliveira EM, Keogh JM, Talbot F, et al. - Examining if the impact of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains obesity, it was found that pathogenic mutations may manifest with obesity alone. Thus, screening for GNAS deficiency in children with severe obesity may permit early diagnosis, improving clinical results, and melanocortin agonists may help in weight loss.

• Of 2,548 children with severe obesity, 22 were GNAS mutation carriers.

• Impairment of MC4R signaling was caused by almost all GNAS mutations.

• Reduced growth was seen in 6 of 11 patients (12 to 18 years aged), and growth hormone–releasing hormone receptor signaling was disrupted due to mutations in these patients.

• Developmental delay and higher thyrotropin levels were evident in relation to GNAS mutations that impaired thyrotropin receptor signaling.

• GNAS mutations, detected via unbiased genetic testing, differentially impact G protein–coupled receptor signaling pathways that add to clinical heterogeneity.

• Monogenic diseases are clinically more variable vs their classic descriptions suggest.