Cortney Gensemer, Tyler Beck, Lilong Guo, Taylor Petrucci, Jordan Morningstar, Isabelle Kornblau, Kathryn Byerly, Rachel Biggs, Amy Weintraub, Kelsey Moore, Natalie Koren, Victoria Daylor, Christina Hastings, Emily Oberlies, Ella R Zientara, Elsie Devey, Sarah Dooley, Kristina Stayer, Roman Fenner, Katherine Singleton, Sofia Luzbetak, Deatra Bear, Rebecca Byrd, Julianna Weninger, Erika Bistran, Gyda Beeson, Joshua Kerns, Molly Griggs, Charlotte Griggs, Madalyn Osterhaus, Emily Fleck, Jillian Schnaudigel, Shaina Butler, Sydney Severance, Wiley Kendall, Joe R Delaney, Daniel P Judge, Peng Chen, Hai Yao, Jan Guz, Alexander Awgulewitsch, Steven A Kautz, Rupak Mukherjee, Robert Price, Fraser Henderson, Steven Shapiro, Clair A Francomano, Jason C Kovacic, Mark Lavallee, Sunil Patel, Takiy-Eddine Berrandou, Susan A Slaugenhaupt, David Milan, Amy R Kontorovich, Nabila Bouatia-Naji, Russell A Norris
{"title":"Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome.","authors":"Cortney Gensemer, Tyler Beck, Lilong Guo, Taylor Petrucci, Jordan Morningstar, Isabelle Kornblau, Kathryn Byerly, Rachel Biggs, Amy Weintraub, Kelsey Moore, Natalie Koren, Victoria Daylor, Christina Hastings, Emily Oberlies, Ella R Zientara, Elsie Devey, Sarah Dooley, Kristina Stayer, Roman Fenner, Katherine Singleton, Sofia Luzbetak, Deatra Bear, Rebecca Byrd, Julianna Weninger, Erika Bistran, Gyda Beeson, Joshua Kerns, Molly Griggs, Charlotte Griggs, Madalyn Osterhaus, Emily Fleck, Jillian Schnaudigel, Shaina Butler, Sydney Severance, Wiley Kendall, Joe R Delaney, Daniel P Judge, Peng Chen, Hai Yao, Jan Guz, Alexander Awgulewitsch, Steven A Kautz, Rupak Mukherjee, Robert Price, Fraser Henderson, Steven Shapiro, Clair A Francomano, Jason C Kovacic, Mark Lavallee, Sunil Patel, Takiy-Eddine Berrandou, Susan A Slaugenhaupt, David Milan, Amy R Kontorovich, Nabila Bouatia-Naji, Russell A Norris","doi":"10.21203/rs.3.rs-4547888/v1","DOIUrl":null,"url":null,"abstract":"<p><p>Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients. A missense variant in <i>Kallikrein-15</i> (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the <i>Kallikrein</i> gene family. To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, <i>Klk15</i> <sup><i>G224D/+</i></sup> mice displayed structural and functional connective tissue defects within multiple organ systems. These findings support <i>Kallikrein</i> gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213194/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Research square","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.21203/rs.3.rs-4547888/v1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients. A missense variant in Kallikrein-15 (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the Kallikrein gene family. To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, Klk15G224D/+ mice displayed structural and functional connective tissue defects within multiple organ systems. These findings support Kallikrein gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.
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