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NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.

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Purpose of Review The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. Recent Findings In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. Summary There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients. Electronic supplementary material The online version of this article (10.1007/s11892-020-01327-7) contains supplementary material, which is available to authorized users.

Background The duodenal-jejunal bypass liner (DJBL) is an endoscopic device designed to induce weight loss and improve glycemic control. The liner is licensed for a maximum implant duration of 12 months. It might be hypothesized that extension of the dwelling time results in added value. The goals of our study were to determine weight change, change in glycemic control, and safety in patients with an intended 24 months of DJBL dwelling time. Methods Patients were initially selected for a 12-month implantation period. When no physical complaints or adverse events (AEs) occurred, motivated patients who responded well were selected for extension of dwelling time to 24 months. Patients underwent a control endoscopy 12 months after implantation and visited the outpatient clinic every 3 months up to explantation. Patients agreed to remove the DJBL when complaints or AEs occurred that could not be treated conservatively. Results Implantation was extended in 44 patients, and 24 (55%) patients completed the full 24 months. Twenty patients required early removal due to AEs. During dwelling time, body weight decreased significantly (15.9 kg; TBWL 14.6%). HbA1c decreased non-significantly (4.9 mmol/mol). The number of insulin users and daily dose of insulin both decreased significantly. At 24 months after removal, glycemic control had worsened, while body weight was still significantly lower compared to baseline. In total, 68% of the patients experienced at least one AE. Two patients developed a hepatic abscess. Conclusions DJBL treatment results in significant weight loss and improves glycemic control during implantation. The largest beneficial effects occur during the first 9-12 months after implantation. Extension of dwelling time to 24 months results only in stabilization of body weight and glycemic control. After explantation, weight improvements are maintained, but glycemic control worsens. As the cumulative risk of AEs increases with time, a maximal dwelling time of 12 months is advisable. Keywords Adverse events • Duodenal-jejunal bypass liner • Diabetes mellitus • Endobarrier • Hepatic abscess • Migration Abbreviations AE Adverse event ASGE American Society of Gastrointestinal Endoscopy DJBL Duodenal-jejunal bypass liner IGB Intragastric balloon SD Standard deviation T2DM Type 2 diabetes mellitus The increasing prevalence of obesity calls for the development of weight control measures. The current mainstay of treatment for morbid obesity is bariatric surgery. Roux-en-Y gastric bypass is one of the most performed bariatric procedures and has proven to be effective in inducing weight loss and controlling comorbidities such as type 2 diabetes mellitus (T2DM) and hypertension [1, 2]. As surgery carries the risk of intra-and postoperative adverse events (AEs), there

Context Single-minded homologue 1 (SIM1) is a transcription factor with several physiological and developmental functions. Haploinsufficiency of SIM1 is associated with early-onset obesity with or without Prader-Willi–like (PWL) features and may exhibit incomplete penetrance. Case Description Next-generation sequencing was performed for 2 male patients with obesity, including 1 man presenting with intellectual disability (ID), body mass index (BMI) of 47.4, and impulse-control disorder, and the other man with early obesity (BMI of 36); sequencing revealed a missense variant in SIM1 (c.2144G>T; p.G715V) in both individuals. Previous studies have identified several disease-associated variants that fall near the p.G715V variant within the C-terminal domain of SIM1. We examined p.G715V variant stability and activity in a doxycycline-inducible stable cell line transfected with an artificial reporter construct and either ARNT or ARNT2 as a partner protein. Conclusions Functional testing of the p.G715V variant revealed a significant reduction in SIM1-mediated transcriptional activity. We also generated the first ab initio hybrid protein model for full-length SIM1 to show the predicted spatial relationship between p.G715V and other previously described variants in this region and identified a putative mutation hotspot within the C-terminus. Significant clinical heterogeneity has been observed in patients with SIM1 variants, particularly with regards to the PWL phenotype. In the patient with ID, a second variant of uncertain significance in CHD2 was identified that may contribute to his ID and behavioral disturbances, emphasizing the role of additional genetic modifiers.

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