[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-462480-105":59,"doc-detail-462480-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","novel-sim1-variants-expanding-the-spectrum-of-sim1-related-obesity","Novel SIM1 Variants - Expanding the Spectrum of SIM1-Related Obesity","","Monogenic forms of severe early-onset obesity often stem from genetic disruptions in the hypothalamic leptin-melanocortin pathway, particularly pathogenic SIM1 variants that cause a Prader–Willi-like presentation. Targeted next-generation sequencing of 52 obesity-associated genes was performed in pediatric patients, followed by population frequency and in silico pathogenicity prediction, including structural assessment using protein modeling with AlphaFold3. Five rare SIM1 variants were found in eleven patients, including frameshift, missense, and a recurrent synonymous splice-altering candidate, emphasizing SIM1 inclusion in testing panels.",{"@graph":69,"@context":123},[70,84,106],{"@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/novel-sim1-variants-expanding-the-spectrum-of-sim1-related-obesity/462480/",{"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/novel-sim1-variants-expanding-the-spectrum-of-sim1-related-obesity/462480.png","ImageObject",300,407,{"name":92,"@type":93},"Bintang","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-10","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the clinical significance of SIM1 variants in severe early-onset obesity?","Question",{"text":113,"@type":114},"Pathogenic SIM1 variants can cause Prader–Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How were the SIM1 variants identified and evaluated in the study?",{"text":118,"@type":114},"The study used targeted next-generation sequencing across 52 obesity-associated genes, then assessed variants by population frequency and predicted pathogenicity with in silico tools, including structural modeling with AlphaFold3.",{"name":120,"@type":111,"acceptedAnswer":121},"What types of SIM1 variants were reported, and what effects were suggested?",{"text":122,"@type":114},"The researchers identified four heterozygous nonsynonymous variants (frameshift and missense) and one recurrent synonymous variant, with modeling suggesting disruption of critical protein interactions and possible splice alteration.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},462480,1791097886,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":105,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":41,"preview_page_count":4},962085564381,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Case Report  \nNovel SIM1 Variants Expanding the Spectrum of SIM1-Related Obesity  \nIdris Mohammed 1,2, Wesam S. Ahmed 1, Tara Al-Barazenji 2, Hajar Dauleh 2, Donald R. Love 3 and Khalid Hussain 2, *  \nAcademic Editor: Łukasz Bułdak  \nReceived: 5 November 2025  \nRevised: 25 December 2025  \nAccepted: 30 December 2025  \nPublished: 5 January 2026  \nCopyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 College of Health & Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; [imohammed-c@sidra.org](imohammed-c@sidra.org) (I.M.); [wisamyejo@yahoo.com](wisamyejo@yahoo.com) (W.S.A.)  \n2 Division of Endocrinology, Department of Pediatric Medicine, Sidra Medicine, Doha P.O. Box 26999, Qatar; [talbarazenji@sidra.org](talbarazenji@sidra.org) (T.A.-B.); [hdauleh1@sidra.org](hdauleh1@sidra.org) (H.D.)  \n3 Division of Genetic Pathology, Department of Pathology, Sidra Medicine, Doha P.O. Box 26999, Qatar; [dlove@sidra.org](dlove@sidra.org)  \n* Correspondence: [khussain@sidra.org](khussain@sidra.org)  \nAbstract  \nMonogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader–Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay. We performed targeted next-generation sequencing of 52 obesityassociated genes on a cohort of pediatric patients with severe early-onset obesity. Identified variants were analyzed for population frequency and predicted pathogenicity using insilico tools. The structural impact of the novel missense variants was assessed using protein domain modeling with AlphaFold3 . We identified five rare SIM1 variants in eleven patients. Four were heterozygous nonsynonymous variants: one frameshift in the bHLH domain (p.Ser18Ter), one frameshift in the Per-ARNT-Sim domain (p.His143Ter), and two missense variants, p.Pro30Ala and p.Ser663Leu. Structural modeling suggested that the missense variants are likely to disrupt critical protein–protein interactions. The fifth variant was a synonymous change, c.1173G>A, p.(Ser391Ser), which was detected in five unrelated patients. Bioinformatic analysis predicted that this variant could alter splicing. Structural modeling suggested that the missense variants interfere with SIM1 function. This study expands the mutational spectrum of SIM1-linked monogenic obesity, reporting novel likely pathogenic frameshift variants, a missense variant, and a recurrent synonymous variant with a potential splice-site effect. The majority of the variants are predicted to affect the SIM1 protein. Our findings strengthen the critical role of the SIM1 gene in hypothalamic development and energy homeostasis. The results underscore the importance of includingthe SIM1 gene in genetic testing panels for children with severe obesity and hyperphagia, enabling precise diagnosis and potential future personalized management. Functional in vitro or in vivo validation of these variants is required to confirm their pathogenicity.  \nKeywords: SIM1; monogenic obesity; leptin-melanocortin; hyperphagia; early-onset obesity; Prader-Willi-like syndrome  \n1. Introduction  \nObesity is a worldwide epidemic with rates nearly tripled over the last three decades among adults and increased almost five times among children and adolescents [1] . Al-  \nthough the primary cause of obesity is complex, an interplay between environmental and polygenic factors, there is considerable evidence of a monogenic contribution [2] . The vast majority of monogenic forms of obesity are due to genetic defects in the hypothalamic leptin-melanocortin signalling pathway, a pathway crucial in regulating appetite, energy regulation, and body ","cbCaildd72Bl3ifO","https://ap.wps.com/l/cbCaildd72Bl3ifO","pdf",773181,"English","# Abstract\n# Introduction","[{\"question\":\"What is the clinical significance of SIM1 variants in severe early-onset obesity?\",\"answer\":\"Pathogenic SIM1 variants can cause Prader–Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay.\"},{\"question\":\"How were the SIM1 variants identified and evaluated in the study?\",\"answer\":\"The study used targeted next-generation sequencing across 52 obesity-associated genes, then assessed variants by population frequency and predicted pathogenicity with in silico tools, including structural modeling with AlphaFold3.\"},{\"question\":\"What types of SIM1 variants were reported, and what effects were suggested?\",\"answer\":\"The researchers identified four heterozygous nonsynonymous variants (frameshift and missense) and one recurrent synonymous variant, with modeling suggesting disruption of critical protein interactions and possible splice alteration.\"}]","Novel SIM1 Variants - Expanding the Spectrum of SIM1-Related Obesity | PDF",1790764203]