Testing for rare genetic causes of obesity: findings and experiences from a pediatric weight management program

Background Genetic screening for youth with obesity in the absence of syndromic findings has not been part of obesity management. For children with early onset obesity, genetic screening is recommended for those having clinical features of genetic obesity syndromes (including hyperphagia). Objectives The overarching goal of this work is to report the findings and experiences from one pediatric weight management program that implemented targeted sequencing analysis for genes known to cause rare genetic disorders of obesity. Subjects/Methods This exploratory study evaluated youth tested over an 18-month period using a panel of 40-genes in the melanocortin 4 receptor pathway. Medical records were reviewed for demographic and visit information, including body mass index (BMI) percent of 95th percentile (%BMIp95) and two eating behaviors. Results Of 117 subjects: 51.3% were male; 53.8% Hispanic; mean age 10.2 years (SD 3.8); mean %BMIp95 157% (SD 29%). Most subjects were self- or caregiver-reported to have overeating to excess or binge eating (80.3%) and sneaking food or eating in secret (59.0%). Among analyzed genes, 72 subjects (61.5%) had at least one variant reported; 50 (42.7%) had a single variant reported; 22 (18.8%) had 2-4 variants reported; most variants were rare (<0.05% minor allele frequency [MAF]), and of uncertain significance; all variants were heterozygous. Nine subjects (7.7%) had a variant reported as PSCK1 risk or MC4R likely pathogenic; 39 (33.3%) had a Bardet-Biedl Syndrome (BBS) gene variant (4 with pathogenic or likely pathogenic variants). Therefore, 9 youth (7.7%) had gene variants previously identified as increasing risk for obesity and 4 youth (3.4%) had BBS carrier status. Conclusions Panel testing identified rare variants of uncertain significance in most youth tested, and infrequently identified variants previously reported to increase the risk for obesity. Further research in larger cohorts is needed to understand how genetic variants influence the expression of non-syndromic obesity.

Automated summary

This study conducted targeted sequencing analysis for genes known to cause rare genetic disorders of obesity in youth. The findings revealed that most youth tested had rare gene variants of uncertain significance, and only a small percentage had gene variants previously identified as increasing the risk for obesity. Further research in larger cohorts is needed to understand how genetic variants influence non-syndromic obesity.