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Abstract :
[en] Introduction: Obesity is a major global health issue with multifactorial etiologies. Among them, recent advances in the understanding of eating behavior and energy regulation have shown that approximately 60 genes involved in the hypothalamic leptin–melanocortin pathway contribute to the development of rare monogenic or syndromic forms of obesity.
Objective: To better delineate the genetic diagnostic yield and phenotypic spectrum in a cohort of patients living with early-onset obesity, and to integrate our findings into guidance for genetic testing.
Methods: In a diagnostic setting, 223 patients living with early-onset obesity were screened using a targeted panel including 44 genes implicated in severe early-onset obesity. Genetic results and clinical descriptions were reviewed for the entire cohort. An additional 64 patients and their genetic results were included in a second phase of the study to assess the consistency and potential evolution of the diagnostic yield.
Results: An initial diagnostic yield of 3.1% was obtained in the first cohort of 223 patients. Likely pathogenic or pathogenic variants were identified in MRAP2, MC4R, BBS2, and BBS4, and a 16p11.2 deletion was confirmed. Clinically, 23% of the cohort presented early-onset obesity before 1 year of age, 47% between 1–4 years, and 30% after 4 years. No discriminative clinical features appeared to enhance the diagnostic yield. Thirty‑six percent of the cohort presented additional neurological features that prompted more extensive genetic investigations, resulting in a diagnostic rate of 1.8% within this subgroup.
Among the 64 patients investigated in the second phase, we identified one likely pathogenic MC4R variant and four highly suspicious class 3 variants. Current evidence from two of these patients supports the hypothesis that their variants may be reclassified as likely pathogenic, given additional clinical data fulfilling further ACMG criteria.
Conclusion: Our work demonstrates a total diagnostic yield ranging between 3.5% and 4.2% (10–12 positive results out of 287 patients). Additionally, in the first phase, 19.7% of heterozygous variants of uncertain significance were detected in genes related to autosomal dominant conditions and 34.9% in genes related to autosomal recessive conditions. These findings underscore the need for accurate genotype–phenotype correlation. Genetic laboratory expertise in obesity is highly recommended, particularly in the context of the availability of new targeted anti-obesity therapies, which expand current and future perspectives for precision genetic evaluation.
