Variant reclassification over time decreases the level of diagnostic uncertainty in monogenic obesity: experience from two centres

Morandi A; Fornari E; Corradi M; Umano GR; Olivieri F; Piona C; Maguolo A; Panzeri C; Emiliani F; Cirillo G; Cavarzere P; Giudice E Miraglia Del; Maffeis C

doi:10.1530/ey.22.11.7

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 11.7 | DOI: 10.1530/ey.22.11.7

ESPEYB25 11. Obesity and Weight Regulation New Genes and their Pathogenicity (3 abstracts)

11.7. Variant reclassification over time decreases the level of diagnostic uncertainty in monogenic obesity: experience from two centres

Morandi A , Fornari E , Corradi M , Umano GR , Olivieri F , Piona C , Maguolo A , Panzeri C , Emiliani F , Cirillo G , Cavarzere P , Miraglia Del Giudice E & Maffeis C

Author affiliations

Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Pediatrics, and Gynecology, University of Verona, Verona, Italy. Department of Woman, Child and of General and Specialized Surgery, University of Campania“Luigi Vanvitelli”, Naples, Italy. Epigenetics and Diabetes Unit, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden. [email protected]

Pediatric Obesity. 2024; 19:e13183. doi: 10.1111/ijpo.13183. https://pubmed.ncbi.nlm.nih.gov/39462520/

Brief Summary: This multicenter observational study showed that the initial genetic variant evaluation uncertainty (overall 30 variants) and the molecular diagnostic uncertainty of monogenic obesity reduced by a third through genetic variant reassessment after three years of baseline classification. This achievement is due to advances in genomic data interpretation, including larger population datasets and knowledge of functional effects in monogenic obesity.

Accurate classification of genetic variants as possible causes for monogenic obesity is important for the diagnosis, for counselling of patients and for therapeutical management with access to new drug therapies. However, the molecular diagnosis of monogenic obesity is burdened by frequent variant uncertainty (e.g. variants of uncertain significance (VUS), likely benign or likely pathogen variants). Morandi et al. emphasize the dynamic of genetic interpretation and show the utility of ongoing variant reevaluation. Chen et al. recently confirmed the necessity of uncertain variant reclassification in context of several rare diseases [1]. As manual adjustment is decisive for the meaningful interpretation of genetic variants and thus the increase of certain classifications (benign and pathogenic variants) a detailed patient phenotyping in monogenic obesity is essential. Guidelines concerning reevaluation frequency and exact method for performing the follow-up of variants should be elaborated for systematically reclassifiing previously identified variants.

Reference: 1. Chen E, Facio FM, Aradhya KW, et al. Rates and classification of variants of uncertain significance in hereditary Disease Genetic testing. JAMA Netw Open. 2023;6(10):e2339571.