ESPE2024 Top 20 Posters Top 20 Posters (19 abstracts)
The importance of genetic diagnosis in obesity - leptin-melanocortin pathway and beyond.
Robert Šket 1,2 , Primož Kotnik 1,2 , Barbara Slapnik 1,2 , Barbara Čugalj Kern 1,2 , Ana Šenica 1 , Barbara Jenko Bizjan 1,2 , Tine Tesovnik 1,2 , Blaž Vrhovšek 1 , Maruša Debeljak 1,2 , Tadej Battelino 1,2 & Jernej Kovač 1,2
1University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia. 2University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
Objective: Determining the cause of early obesity in children is of paramount importance for early and efficient treatment, including novel targeted pharmaceutical treatment options (e.g. MCR4 agonist). Here, we report findings from diagnostic whole exome sequencing of children with obesity, identifying genetic variants both within and outside the leptin-melanocortin pathway associated with obesity. These findings provide valuable insights for informed pharmacological treatment decisions.
Methods: 485 children with obesity (BMI SDS > 2) aged 2 to 18 years were included. Clinical assessments included detailed anthropometric measurements, dietary intake, physical activity levels, and family history of obesity. Whole exome next-generation sequencing was performed on the NovaSeq (Illumina), and data were analyzed using a robust bioinformatics pipeline, with alignment (BWA-MEM) to the reference genome (GRCh37), variant calling (ANNOVAR), and functional annotation (OMIM, HPO, GTEx, Gene Ontology).
Results: Variants in key genes of the leptin-melanocortin pathway, including LEPR, POMC, PCSK1, ADCY3, SIM1, MC3R, and MC4R, with a total of nine disease-causing variants (DCVs) and fourteen variants of unknown significance (VUS) were identified in 4.7 % of children (average BMI SDS of 3.1 ± 0.6 (mean ± SD)). Additionally, genes associated with obesity outside of the leptin-melanocortin pathway were identified in 5.6 % of children. Eight children were carriers of DCVs and nineteen were carriers of VUS in genes such as SH2B1, KSR2, NTRK2, VPS13B, INPP5E, GIPR, MED13L, GNAS, BDNF, BBS5, CHRNA7, GHSR, MAGEL2, MTHFR, and ATP7B. The corresponding BMI SDS averaged 3.1 ± 0.9. Notably, DCVs in GNAS were identified in two patients.
Conclusion: By considering genes associated with obesity in addition to those in the leptin-melanocortin pathway, we have doubled the number of diagnosed children with obesity, thereby improving our diagnostic yield. Information about the presence of genetic variants indicates targeted pharmacological intervention, either with MC4R agonists for genes in the leptin-melanocortin pathway or with other pharmacological agents for genetic variants outside this pathway.
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