Clinical and Biological Phenotypes of Patients Carrying a Heterozygous Variant in Genes of Leptin-Melanocortin Signaling Pathway

BACKGROUND: Obesity is a multifactorial condition and represents a major public health issue. In 5% of cases, obesity is monogenic, secondary to an abnormality in a gene of the leptin-melanocortin signaling pathway. OBJECTIVES: The aim of our retro-prospective descriptive study is to reclassify heterozygous variants of unknown significance (VUS) and to describe the clinical and biological phenotypes of the patients carrying these variants. METHODS: Our study population included adult and pediatric patients followed in the Hospices Civils de Lyon for severe obesity, with a heterozygous probably pathogenic variant or a variant of unknown significance on a specific gene of interest identified by genetic analysis between January 2018 and December 2022. Reclassification of variants was based on family segregation and the recent literature data. The data concerning medical history, phenotypic characteristics, and biological results were extracted from medical files. RESULTS: Twenty-six patients underwent family segregation analysis: 10 patients were identified as carriers of a heterozygous probably pathogenic variant or VUS with a positive segregation. All patients had early-onset obesity at a mean age of 2.8 years. CONCLUSIONS: Our study highlights the clinical relevance of family segregation in reclassifying VUS within the leptin-melanocortin pathway and underscores the diagnostic value of early obesity onset in identifying potential monogenic forms.