MON-722 Similar BMI Trends Identified in Family Members of Patients who Have Rare Genetic Obesity Variants

Abstract Disclosure: M. Berra: None. E. Volcotrub: None. S.B. Ten: None. A.S. Bhangoo: None. Introduction: With the rise of availability of genetic testing, we are identifying patients with early onset obesity who have one or multiple heterozygous variants in the genes associated with rare syndromic obesity. These syndromes are typically inherited in autosomal recessive fashion. We are exploring the phenotypes in children with these variants and are obtaining parental testing to delineate if parents with the same variant have similar phenotypes. Methods: 405 children and young adults with early onset obesity at 2 institutions had genetic testing through Prevention Genetics/Rhythm Pharmaceuticals Rare Obesity sponsored program which screens for 87 genes. Results: In 14 patients from 12 families (2 families with a set of siblings) who had a variant identified on testing, we have performed genetic testing of parents. We included data on parents who were found to have the same variants as the probands. One each of the variants was classified as pathogenic, likely pathogenic and at risk. 9 others were classified as variants of uncertain significance (VUS). All variants were heterozygous and also found in one of the parents. The variants were found in many genes including BBS2, BBS16, VPS13B, SEMA3G, KSR2, ARL6, POMC, PLXNA4, BBS14, MC3R, MCR4, NTRK2. The average BMI of the probands was 39.2 ±10.3 kg/m2. BMI was their parents was higher 42.9 ±10.6 kg/m2 but not significantly different. BMI in the parents ranged from 25.25 to 54. 2 of the parents had normal BMI, none in overweight, 2 with class I obesity, 8 in Class III obesity. The BMI of the parents with VUS ranged from 25.9 to 54 with 1 with normal BMI, only 2 in class I obesity and the remaining 6 in Class III obesity. Conclusion: Majority of the parents carrying variants as VUS had higher BMI. The majority of children with severe obesity with VUS had parents with severe Class III obesity as well. Although these heterozygous variants are not known to cause syndromic obesity, there is a strong familial incidence of obesity in those with the same variant. These VUS with strong family h/o severe obesity need to be further studied for functional studies and genotype/phenotype correlation may help us better understand comorbidity risk or possibly guide treatment modality. Presentation: Monday, July 14, 2025