{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:59:38Z","timestamp":1791464378007,"version":"4.3.4"},"reference-count":34,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100031562","name":"Soci\u00e9t\u00e9 Fran\u00e7aise de P\u00e9diatrie","doi-asserted-by":"publisher","award":["18000 \u20ac"],"award-info":[{"award-number":["18000 \u20ac"]}],"id":[{"id":"10.13039\/100031562","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Obesity"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in five established leptin\u2010melanocortin pathway genes (\n                      <jats:italic>LEP, LEPR, MC4R, PCSK1<\/jats:italic>\n                      ,\n                      <jats:italic>POMC<\/jats:italic>\n                      ) are associated with severe early\u2010onset obesity and are targets for emerging treatments. However, these variants are rare in these patients, suggesting the involvement of additional genes interacting with this pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Next\u2010generation sequencing (NGS) analysis was performed in 395 patients with severe obesity, including 213 children (mean BMI: 56.3\u2009kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      ; BMI\u2010\n                      <jats:italic>z<\/jats:italic>\n                      \u2010score: 4.6). The analysis targeted 20 genes, including the 5 established genes. Rare genetic variants were assessed for pathogenicity using prediction algorithms, genetic databases, and literature review. Phenotypic data were retrospectively collected, focusing on obesity severity, age of onset, familial history, eating behavior disorder, neurodevelopmental and endocrine\u2010associated diseases, and obesity complications.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Pathogenic heterozygous variants were identified in 34 patients (8.6%), 18 of them harboring pathogenic variants in the 15 additional genes. In adults, early\u2010onset obesity was more frequent in potentially pathogenic variants carriers than in non\u2010carriers (83.3% vs. 55.0%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04). No differences were observed in the other phenotypic characteristics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This supports the relevance of expanded genetic testing in severe obesity. Early\u2010onset obesity remains a key clinical feature to guide genetic investigation and identify patients who may benefit from early personalized care and targeted treatments.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/oby.70107","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T11:55:51Z","timestamp":1766750151000},"page":"499-511","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeted Next\u2010Generation Sequencing of the Leptin\u2010Melanocortin Pathway in Severe Obesity"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1230-5675","authenticated-orcid":false,"given":"Nathan","family":"Faccioli","sequence":"first","affiliation":[{"name":"AP\u2010HP, Trousseau Hospital, Department of Pediatric Nutrition and Gastroenterology, Reference Center for Rare Diseases PRADORT (Prader\u2010Willi Syndrome and Other Rare Forms of Obesity With Eating Behavior Disorders) Sorbonne University  Paris France"},{"name":"INSERM, Nutrition and Obesity: Systemic Approaches, NutriOmics Research Unit Sorbonne University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrisitne","family":"Poitou","sequence":"additional","affiliation":[{"name":"INSERM, Nutrition and Obesity: Systemic Approaches, NutriOmics Research Unit Sorbonne University  Paris France"},{"name":"AP\u2010HP, Pitie\u2010Salpetriere Hospital, Nutrition Department, Reference Center for Rare Diseases (PRADORT, Prader\u2010Willi Syndrome and Other Rare Forms of Obesity With Eating Behavior Disorders) Sorbonne University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Georget","sequence":"additional","affiliation":[{"name":"AP\u2010HP, Pitie\u2010Salpetriere Hospital, Functional Unit for the Genetics of Obesity and Dyslipidemia, Endocrine and Oncology Biochemistry Department Sorbonne University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Bertin","sequence":"additional","affiliation":[{"name":"AP\u2010HP, Pitie\u2010Salpetriere Hospital, Functional Unit for the Genetics of Obesity and Dyslipidemia, Endocrine and Oncology Biochemistry Department Sorbonne University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahlam","family":"Azar\u2010Kolakez","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetology, Reference Center for Growth and Development Endocrine Diseases University Paris Cite, AP\u2010HP, Robert Debre University Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8175-0369","authenticated-orcid":false,"given":"Claire","family":"Carette","sequence":"additional","affiliation":[{"name":"AP\u2010HP, Georges Pompidou European Hospital, Department of Nutrition, Specialized Obesity Centre &amp; INSERM UMRS 1149 University Paris Cite  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Faucher","sequence":"additional","affiliation":[{"name":"INSERM, Nutrition and Obesity: Systemic Approaches, NutriOmics Research Unit Sorbonne University  Paris France"},{"name":"AP\u2010HP, Pitie\u2010Salpetriere Hospital, Nutrition Department, Reference Center for Rare Diseases (PRADORT, Prader\u2010Willi Syndrome and Other Rare Forms of Obesity With Eating Behavior Disorders) Sorbonne University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7399-1330","authenticated-orcid":false,"given":"Blandine","family":"Gatta\u2010Cherifi","sequence":"additional","affiliation":[{"name":"Haut Leveque Hospital, Department of Endocrinology, Diabetology, Metabolic Diseases and Nutrition University of Bordeaux  Pessac 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