OR22-05 Rare Biallelic Variants in Obesity-Related Genes in the Madrid Pediatric Obesity Cohort
Journal of the Endocrine Society
BACKGROUND: Obesity is a heterogenous disease resulting from environmental and genetic factors and is characterized by disordered energy balance, regulated in part by the hypothalamic melanocortin-4 receptor (MC4R), including neuronal ciliary assembly and trafficking pathways.1 Rare loss-of-function variants in genes encoding components of this pathway are associated with severe obesity and hyperphagia, with or without additional features.2 However, such rare genetic disorders may be
... s may be underestimated due to a lack of genetic screening in individuals with severe obesity.3 Our objective was to identify and characterize rare genetic variants in a Spanish population from Madrid with childhood obesity. Methods: This analysis was conducted from a prospectively-collected cohort of children with obesity, generally with a BMI>+3DS. Participants were sequenced for 35 obesity-related genes, including 23 genes related to Bardet-Biedl (BBS) and Alström syndromes, plus an additional 12 genes associated with non-syndromic, monogenic causes of obesity, to identify individuals with rare (<1% frequency in gnomAD) potentially biallelic (homozygous and compound heterozygous) non-synonymous variants in protein-coding regions. Results: Of the 1019 Spanish patients with obesity, 493 (48.4%) were female and the mean age and BMI were 10.41 ± 3.38 years and 4.38 ± 1.76 SDS (79.8% above +3 SDS), respectively. We identified 26 rare potentially biallelic variants in 25 unique individuals, including 2 individuals with homozygous variants in POMC, 3 individuals with two variants in SRC1, one individual with two variants in ADCY3, and one individual with a homozygous mutation in LEP. In addition, we identified 18 individuals with biallelic mutations in one of 23 BBS or ALMS1 genes, including two individuals with known pathogenic variants and clinically confirmed BBS. Conclusions: Rare and potentially biallelic sequence variants were identified in 25 individuals with childhood obesity. These results support the use of genetic testing for individuals with severe obesity who may be candidates for specific clinical interventions or additional targeted therapies.