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Purpose <p>To investigate the prevalence, classification, and clinical impact of genetic variants in leptin–melanocortin (MC4R) pathway- and ciliopathy related genes, and in some key neurodevelopmental and pleiotropic genes whose dysfunction may cause hyperphagia in a sample of youths with severe obesity regardless of age of obesity onset and presence of hyperphagia.</p> Methods <p>Cross-sectional evaluation of patients consecutively referred for severe obesity having had prior next-generation sequencing targeting genes of interest as for the Rare Obesity Advanced Diagnosis (ROAD) program gene panel. Variants were classified according to guidelines as likely benign (LB), pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VOUS). Clinical and metabolic features were compared across groups of controls (mutant negative and LB carriers), VOUS, and LP/P carriers.</p> Results <p>A total of 164 patients were included: 91 patients (54.5%) carried at least one variant. Most variants were heterozygous and classified as VOUS (n = 82, 89%); 10 patients (11%) had LP/P variants. Genes most frequently associated with LP/P findings included <i>MC4R (n</i> = <i>2)</i>, <i>ALMS1 (n</i> = <i>3)</i>, and <i>CEP290 (n</i> = <i>2)</i>. No significant differences were found across groups in obesity degree, lipid profile, glucose metabolism, or behavioural symptoms. A non-significant trend toward earlier onset of obesity was observed in the LP/P group. </p> Conclusion <p>Children with severe obesity often carry gene variants in the leptin–MC4R pathway or associated to ciliopathies, which appear even in cohorts unselected for early onset or hyperphagia. Their clinical significance remains uncertain. Although genetic testing may inform clinical stratification and personalised treatment, its integration into the diagnostic workup of severe obesity should currently be restricted to specialised obesity clinics and research contexts. Findings highlight the need for improved interpretation of LP and VOUS through functional studies and long-term phenotyping.</p>

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Variants in the leptin-MC4R pathway and ciliopathy-related genes in youths with obesity beyond hyperphagia and early onset

  • 期刊论文

  • 发表日期：

    2026年7月9日

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  • Melania Manco,
  • Lucilla Ravà,
  • Alessia Aureli,
  • Vittorio Scoppola,
  • Michela Mariani,
  • Francesco d’ Aniello,
  • Stefano Cianfarani,
  • Danilo Fintini

摘要

Purpose

To investigate the prevalence, classification, and clinical impact of genetic variants in leptin–melanocortin (MC4R) pathway- and ciliopathy related genes, and in some key neurodevelopmental and pleiotropic genes whose dysfunction may cause hyperphagia in a sample of youths with severe obesity regardless of age of obesity onset and presence of hyperphagia.

Methods

Cross-sectional evaluation of patients consecutively referred for severe obesity having had prior next-generation sequencing targeting genes of interest as for the Rare Obesity Advanced Diagnosis (ROAD) program gene panel. Variants were classified according to guidelines as likely benign (LB), pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VOUS). Clinical and metabolic features were compared across groups of controls (mutant negative and LB carriers), VOUS, and LP/P carriers.

Results

A total of 164 patients were included: 91 patients (54.5%) carried at least one variant. Most variants were heterozygous and classified as VOUS (n = 82, 89%); 10 patients (11%) had LP/P variants. Genes most frequently associated with LP/P findings included MC4R (n = 2), ALMS1 (n = 3), and CEP290 (n = 2). No significant differences were found across groups in obesity degree, lipid profile, glucose metabolism, or behavioural symptoms. A non-significant trend toward earlier onset of obesity was observed in the LP/P group.

Conclusion

Children with severe obesity often carry gene variants in the leptin–MC4R pathway or associated to ciliopathies, which appear even in cohorts unselected for early onset or hyperphagia. Their clinical significance remains uncertain. Although genetic testing may inform clinical stratification and personalised treatment, its integration into the diagnostic workup of severe obesity should currently be restricted to specialised obesity clinics and research contexts. Findings highlight the need for improved interpretation of LP and VOUS through functional studies and long-term phenotyping.