Introduction  Monogenic mutations in genes part of the leptin-melanocortin pathway are proven to cause obesity, with the highest reported prevalence among pediatric cohorts. The prevalence in (morbid obese) bariatric patients and the extent in which these mutations alter the weight loss response after bariatric surgery is still largely unknown. The aim of this study is to determine the prevalence of a genetic obesity diagnosis in a large bariatric cohort and evaluating the outcomes after bariatric surgery.

Methods   A custom NGS-assay aimed at enrichment of 255 known obesity genes or putative obesity candidate genes was developed. Analysis of 52 obesity associated genes was performed as a diagnostic gene panel-test by a specialized genome diagnostics laboratory. Patient inclusion criteria were: revisional surgery for insufficient weight loss, BMI > 50kg/m² or childhood age of onset of obesity. Genomic DNA of 1014 patients was sequenced at > 100X median coverage, yielding a 15X horizontal gene panel coverage of >95%.

Results   Multiple known pathogenic mutations and genetic variants of uncertain clinical significance (VUS) were identified. In 26 patients a definitive genetic obesity diagnosis could be established due to a heterozygous mutation in MC4R, POMC and PCSK1. In 61% of the patients a primary Roux-en-Y Gastric Bypass was performed. After two years, mean %Total Body Weight Loss (%TBWL) of 32.6%(±7.5) was achieved, compared to 33.8% (± 9.4) (p=0.736) in patients without mutations on the gene panel.

Conclusion   Clinical effects of mutations in these three genes appear not to interfere with the effectiveness of bariatric surgery in the first two years of follow-up. However, extension of follow-up is necessary to assess the long term effect.  In parallel, analysis of VUS of the 52 obesity associated genes with their effect on weight loss will be performed. Analysis of the 203 (candidate) obesity associated genes could uncover novel genetic causes of obesity. Results from these studies can potentially be used to develop personalized treatment.