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The report describes a four-generation family in which genetic testing identified a likely pathogenic MC4R variant shared with three ancestors, guiding care and informing at-risk relatives across generations.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/monogenic-obesity-due-to-mc4r-deficiency-lessons-from-a-multigenerational-case/443415/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/monogenic-obesity-due-to-mc4r-deficiency-lessons-from-a-multigenerational-case/443415.png","ImageObject",300,407,{"name":92,"@type":93},"Miles","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is MC4R deficiency often underdiagnosed in monogenic obesity?","Question",{"text":112,"@type":113},"MC4R deficiency is common as a monogenic cause of obesity, but it remains underdiagnosed. Patients often go through years of ineffective lifestyle interventions before a causal genetic diagnosis is made.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was the MC4R variant identified in the multigenerational case?",{"text":117,"@type":113},"A genetic panel was performed in the 7-year-old index patient, and relatives were assessed using targeted analysis of the familial MC4R variant by Sanger sequencing.",{"name":119,"@type":110,"acceptedAnswer":120},"What treatment and outcomes were reported after the genetic diagnosis?",{"text":121,"@type":113},"After identifying the variant, liraglutide treatment (3.0 mg/day) was started at age 8, leading to a marked reduction in BMI during the first year. 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Molecular and Cellular Pediatrics (2026) 13:3  \n[https://doi.org/10.1186/s40348-025-00214-z](https://doi.org/10.1186/s40348-025-00214-z)  \nMolecular and Cellular Pediatrics  \nRESEARCH Open Access  \nMonogenic obesity due to MC4R deficiency: lessons from a multigenerational case  \nEleni Z. Giannopoulou 1,2, Stefanie Zorn 1,2,3, Melanie Schirmer 1,2,3, Stephanie Brandt-Heunemann 1,2,3, Julia von Schnurbein 1,2, Claudia Nestoris4, Abubakar Moawia5, Reiner Siebert3,5, Christian Denzer 1,2 and Martin Wabitsch 1,2,3*  \nAbstract  \nBackground Melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity, yet remains underdiagnosed. Patients with monogenic obesity often undergo a frustrating diagnostic and therapeutic odyssey of years of ineffective lifestyle interventions before a causal diagnosis is made. We report a four-generation family where genetic testing in a child identified a likely pathogenic MC4R variant also carried by three ancestors. Methods The studied family included a 7-year-old index patient, her mother, grandmother, and great-grandmother with a history of early-onset obesity. Panel sequencing of monogenic obesity genes was performed in the index patient whereas in the relatives targeted analysis of the familial MC4R variant was performed by Sanger sequencing. Results The index patient developed severe obesity by age 2 years, with hyperphagia, tall stature, and dyslipidemia. Despite lifestyle interventions, her body mass index (BMI) continued to increase. At the age of 7 years, genetic panel testing identified a rare monoallelic variant in the MC4R gene c. 913C >T; p.Arg305Trp, previously shown to impair receptor function. Treatment with liraglutide (3 . 0 mg/day) was initiated at age 8 years, resulting in marked reduction in BMI during the first year of treatment. Subsequent genetic testing of family members identified the same variant in her mother, grandmother, and great-grandmother, all of whom had a history of early-onset obesity and related comorbidities, consistent with segregation of the variant within the family.  \nConclusions This case underscores the importance of early genetic testing in severe childhood obesity to avoid ineffective treatments and enable targeted therapies (e. g., GLP-1 analogues) . Diagnosing (likely) pathogenic MC4R variants can also identify at-risk relatives, providing psychological and clinical benefits across generations.  \nKeywords Monogenic obesity, Liraglutide, Melanocortin 4 receptor  \n*Correspondence:  \nMartin Wabitsch  \n[Martin.Wabitsch@uniklinik-ulm.de](Martin.Wabitsch@uniklinik-ulm.de)  \n1Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany  \n2Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, Center for Rare Endocrine Diseases, Ulm University, Ulm, Germany  \n3German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany  \n4Endokrinologikum Hannover, Hannover, Germany  \n5Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, ","cbCaicM2mDmUTRIz","https://ap.wps.com/l/cbCaicM2mDmUTRIz","pdf",1661324,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# Keywords","[{\"question\":\"Why is MC4R deficiency often underdiagnosed in monogenic obesity?\",\"answer\":\"MC4R deficiency is common as a monogenic cause of obesity, but it remains underdiagnosed. Patients often go through years of ineffective lifestyle interventions before a causal genetic diagnosis is made.\"},{\"question\":\"How was the MC4R variant identified in the multigenerational case?\",\"answer\":\"A genetic panel was performed in the 7-year-old index patient, and relatives were assessed using targeted analysis of the familial MC4R variant by Sanger sequencing.\"},{\"question\":\"What treatment and outcomes were reported after the genetic diagnosis?\",\"answer\":\"After identifying the variant, liraglutide treatment (3.0 mg/day) was started at age 8, leading to a marked reduction in BMI during the first year. The same variant was also found in other affected family members, consistent with segregation within the family.\"}]","Monogenic obesity due to MC4R deficiency - lessons from a multigenerational case | PDF",1790703952]