Biochemical Loss-of-Function Data for SIM1 Increases Probability of Clinical Weight Loss Response to the MC4R Agonist Setmelanotide
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Single-minded homolog 1 (SIM1) is a transcription factor expressed by most neurons of the paraventricular nucleus of the hypothalamus (PVH) and is critical for their development. Within the PVHSIM1 neuron population, melanocortin-4 receptor (MC4R) neurons are key regulators of satiety and body weight. Rare loss-of-function (LOF) variants in SIM1 are associated with early-onset, severe obesity and hyperphagia. Among ~50,000 individuals with severe obesity whose genes were sequenced through a sponsored genetic testing program, 243 unique SIM1 missense variants were identified in 594 patients (1.3% of all participants). Of these, 20 patients with 17 unique variants were enrolled into the DAYBREAK clinical weight loss trial. Here, in a retrospective analysis, we tested if experimentally derived biochemical data assessing the impact of these variants on SIM1 function (ACMG criteria PS3) are predictive of patient response to the MC4R agonist setmelanotide.
Methods:
Functional impact of 213 unique SIM1 missense variants was assessed using a previously reported luciferase reporter gene assay. Results of the assay were validated against previously published data. Clinical response was defined as a ≥5% change in body mass index (BMI) from baseline to Week 16 of the trial.
Results:
Twenty patients carrying one of 17 unique, rare SIM1 variants were enrolled in the DAYBREAK trial (15 classified as variants of uncertain significance [VUS] and 2 as likely pathogenic according to ACMG criteria). Overall, 5 of 20 patients achieved a ≥5% reduction in BMI at 16 weeks (a 25% response rate). We performed a post hoc analysis of the response data to determine if in vitro functional assay results were predictive of outcome. Data were available for 13 variants carried by 16 patients. Seven of the 13 unique variants were predicted to retain wild-type (WT) activity, and 6 were predicted to result in moderate or severe LOF. All 7 patients carrying the 7 WT variants either discontinued the trial or showed no reduction in BMI. Of the 9 patients carrying one of the 6 variants predicted to be LOF, 4 of 9 (44%) responded to treatment. Of note, the p.Asp707His variant, previously reported as moderately damaging and of variable penetrance, was observed in 3 patients who achieved a wide range of percent changes in BMI at 16 weeks (−15.1%, −3.3%, and +1.1%), thus accounting for 2 of 5 nonresponders carrying LOF variants. Similar results were observed in an analysis of the 16 patients who completed 16 weeks of treatment. Five of 16 patients achieved a ≥5% reduction in BMI at 16 weeks (a 31% response rate). Ten of the unique variants identified were functionally characterized. Excluding WT and uncharacterized variants from the analysis, 8 patients carried LOF variants, 4 of whom were responders (a 50% response rate). Two of the 4 nonresponders with LOF variants carried the variable-penetrance p.Asp707His allele.
Conclusion:
These data show the importance of functional characterization of VUS in SIM1 for the interpretation of the clinical significance of the VUS and potential value when considering treatment with setmelanotide.
Single-minded homolog 1 (SIM1) is a transcription factor expressed by most neurons of the paraventricular nucleus of the hypothalamus (PVH) and is critical for their development. Within the PVHSIM1 neuron population, melanocortin-4 receptor (MC4R) neurons are key regulators of satiety and body weight. Rare loss-of-function (LOF) variants in SIM1 are associated with early-onset, severe obesity and hyperphagia. Among ~50,000 individuals with severe obesity whose genes were sequenced through a sponsored genetic testing program, 243 unique SIM1 missense variants were identified in 594 patients (1.3% of all participants). Of these, 20 patients with 17 unique variants were enrolled into the DAYBREAK clinical weight loss trial. Here, in a retrospective analysis, we tested if experimentally derived biochemical data assessing the impact of these variants on SIM1 function (ACMG criteria PS3) are predictive of patient response to the MC4R agonist setmelanotide.
Methods:
Functional impact of 213 unique SIM1 missense variants was assessed using a previously reported luciferase reporter gene assay. Results of the assay were validated against previously published data. Clinical response was defined as a ≥5% change in body mass index (BMI) from baseline to Week 16 of the trial.
Results:
Twenty patients carrying one of 17 unique, rare SIM1 variants were enrolled in the DAYBREAK trial (15 classified as variants of uncertain significance [VUS] and 2 as likely pathogenic according to ACMG criteria). Overall, 5 of 20 patients achieved a ≥5% reduction in BMI at 16 weeks (a 25% response rate). We performed a post hoc analysis of the response data to determine if in vitro functional assay results were predictive of outcome. Data were available for 13 variants carried by 16 patients. Seven of the 13 unique variants were predicted to retain wild-type (WT) activity, and 6 were predicted to result in moderate or severe LOF. All 7 patients carrying the 7 WT variants either discontinued the trial or showed no reduction in BMI. Of the 9 patients carrying one of the 6 variants predicted to be LOF, 4 of 9 (44%) responded to treatment. Of note, the p.Asp707His variant, previously reported as moderately damaging and of variable penetrance, was observed in 3 patients who achieved a wide range of percent changes in BMI at 16 weeks (−15.1%, −3.3%, and +1.1%), thus accounting for 2 of 5 nonresponders carrying LOF variants. Similar results were observed in an analysis of the 16 patients who completed 16 weeks of treatment. Five of 16 patients achieved a ≥5% reduction in BMI at 16 weeks (a 31% response rate). Ten of the unique variants identified were functionally characterized. Excluding WT and uncharacterized variants from the analysis, 8 patients carried LOF variants, 4 of whom were responders (a 50% response rate). Two of the 4 nonresponders with LOF variants carried the variable-penetrance p.Asp707His allele.
Conclusion:
These data show the importance of functional characterization of VUS in SIM1 for the interpretation of the clinical significance of the VUS and potential value when considering treatment with setmelanotide.