ESPE2024 Poster Category 2 Fat, Metabolism and Obesity (39 abstracts)
Diagnosis of monogenic obesity: the uncertainty due to the occurrence of VUS has decreased over time. A single center experience of variant follow-up.
Anita Morandi 1 , Elena Fornari 2 , Massimiliano Corradi 1 , Francesca Olivieri 2 , Claudia Piona 1 , Alice Maguolo 1 , Carola Panzeri 1 , Federica Emiliani 2 , Paolo Cavarzere 2 & Claudio Maffeis 1
1University of Verona, Verona, Italy. 2University Hospital of Verona, Verona, Italy
Background: The diagnosis of monogenic obesity is burdened by frequent variants of uncertain significance (VUS). We aim ed to describe our real-life approach of variant re-assessment over time for managing classification uncertainty in the diagnosis of monogenic obesity, and to infer if population data updates and novel functional evidence are decreasing inconclusive variants.
Methods: We tested 101 children/adolescents (11.7[7.3-13.7] years, 3.6[3.3-4.0] z-BMI) for monogenic obesity from January 2020 to February 2023, sequencing LEPR, POMC, ADCY3, PCSK1, CARTPT, SIM1, MRAP2, LEP, NTRK2, BDNF, KSR2, MAGEL2, SH2B1, MC4R, MC3R. In February 2024 we re-assessed the found variants by updated software interpretation and literature renavigation.
Results: We initially found 11 VUS, 3 Likely Pathogenic (LP), 4 Likely Benign (LB), and 1 benign variant in 19 individuals. At follow-up, 4 VUS were reclassified as benign/LB, one LP as pathogenic, and 2 LB as benign, thanks to novel population data and functional evidence. Overall, 7/19 variants were reclassified into a less uncertain category. Monogenic obesity was diagnosed in four unrelated probands carrying two variants at MC4R and one at NTRK2.
Conclusion: Our variant re-assessment was effective to improve classification certainty and highlighted that the molecular diagnosis of monogenic obesity is becoming more accurate over time.
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