Endocrine Abstracts

Introduction: Genetic testing can improve the diagnosis of rare genetic diseases of obesity and identify patients who may benefit from targeted therapeutic intervention. For example, patients with genetic defects in the melanocortin-4 (MC4R) pathway may present with severe early-onset obesity and hyperphagia. Historically, however, genetic testing in patients with obesity has been limited. The Uncovering Rare Obesity® diagnostic genetic testing program aims to enhance access to genetic testing for these patients. The frequency of rare genetic variants in this clinical patient population is currently unknown.

Methods: We sequenced 8599 individuals with severe, early-onset obesity as part of the US-based Uncovering Rare Obesity® program. Genes selected include those with well-established associations with obesity, as well as genes associated with the MC4R pathway. In this program, we sequenced 7811 individuals for 40 genes, and recently expanded the gene panel to include an additional 39 genes and the 16p11.2 chromosomal region; 788 individuals have been sequenced on the broader panel. Yield estimates were weighted by the number of individuals sequenced for each gene.

Results: Integrating across the two panels using weighted yield estimates, 54.6% of sequenced individuals had variants that may qualify them for commercial or investigational treatment with the MC4R agonist setmelanotide. An additional 9.9% of individuals had variants not eligible for setmelanotide treatment, but that may support a genetic diagnosis of obesity. Overall, 2.7% of individuals carried pathogenic or likely pathogenic variants that also met mode of inheritance criteria (2 or more alleles in autosomal recessive conditions and 1 or more alleles in autosomal dominant conditions).

Conclusions: In this selected cohort of individuals with severe, early-onset obesity, 64.5% carried potentially clinically relevant variants. As additional data become available about the investigational genes and obesity, and/or as new obesity-related genes are identified, these estimates may change. Genetic testing of patients with severe obesity, particularly those with a history of early-onset obesity suggestive of a potential genetic origin, may therefore be an important component of understanding the etiology of these patients’ phenotypes, and may potentially impact the course of care for these patients.