ESPE2024 Rapid Free Communications Fat, Metabolism and Obesity 1 (6 abstracts)
Genetic Diagnostic Yield of Obesity
Robert Künzel 1 , Helene Faust 1 , Matthias Blüher 2,3 , Eric Wenzel 4 , Rami Abou Jamra 1 , Mariami Jasaszwili 4 , Anna Kirstein 4 , Albrecht Kobelt 5 , Antje Körner 3,4 , Johannes Lemke 1 , Robert Stein 3,4 , Antje Garten 4 & Diana Le Duc 1,5
1University of Leipzig Medical Center, Institute of Human Genetics, Leipzig, Germany. 2University of Leipzig Medical Center, Medical Department III—Endocrinology, Nephrology, Rheumatology, Leipzig, Germany. 3Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany. 4University Hospital for Children and Adolescents, Pediatric Research Center, Leipzig, Germany. 5Chemnitz Clinic, Diagnostic Center GmbH MVZ, Practice for Human Genetics, Chemnitz, Germany
Background/Objectives: Obesity poses a major public health concern. Although studies estimate that the heritability of BMI lies around 40–50%, the underlying genetics are still poorly understood. In monogenic obesity, solitary genetic variations significantly increase obesity risk. We therefore aim to (1) report the diagnostic yield of monogenic obesity using exome-wide data in a large cohort of over 500 individuals and aim to (2) improve future diagnostic yield by determining predictors of a positive genetic obesity diagnosis.
Methods/Patients: 521 patients with reported obesity underwent genetic diagnostics at the Institute of Human Genetics at Leipzig University between 2016 and 2023. The cohort includes 396 children and 125 adults. 299 patients with obesity also showed developmental delay (DD), intellectual disability (ID) and/or dysmorphisms, 222 patients were without these features. Of the 390 patients whose BMI was known, 262 had severe obesity and 128 had milder obesity. 84.7% of patients (n = 448) received whole exome analyses. The remaining 15.3% (n = 81) underwent diagnostics based on the TruSight One Sequencing Panel (4813 genes).
Results: 5.6% of patients (n = 29) received a definitive monogenic obesity diagnosis. Eight of these patients had MC4R variants, five patients had a 16p11.2 microdeletion. Three patients carried variants in SRRM2, a gene recently associated with obesity. A possible obesogenic variant was reported in a further 7.3% of patients (n = 38). Affected genes include KSR2 and NCOA1. Further research is needed to identify the relevance of these variants. Definitive diagnostic yield was higher in children (6.1%) compared to adults (4%). Additionally, yield was higher in patients with DD, ID and/or dysmorphisms compared to those without these features (6.7% and 4.1% respectively). Finally, diagnostic yield was not increased in severe obesity compared to less severe obesity (3.6% and 4.2%).
Conclusions: 5.6% of patients with obesity received a monogenetic diagnosis. Several other identified variants may increase susceptibility to obesity. A diagnosis of genetic obesity does not seem to become more likely with higher BMI, suggesting that genetic testing should not be limited to cases of extreme obesity. Genetic diagnostic yield was higher in children and in patients with additional DD, ID and/or dysmorphisms, suggesting that testing in these groups should be performed less restrictively.
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