{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:35:38Z","timestamp":1760236538443,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,28]],"date-time":"2021-11-28T00:00:00Z","timestamp":1638057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Introduction: Cardiomyopathies are diseases of the heart muscle and are important causes of heart failure. Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy that can be acquired, syndromic or non-syndromic. The current study was conducted to explore the genetic defects in a Pakistani family with cardiac disease and features of Marfan\u2019s syndrome (MFS). Methods: A family with left ventricle (LV) diastolic dysfunction and MFS phenotype was assessed in Pakistan. The clinical information and blood samples from the patients were collected after physical, cardiovascular, and ophthalmologic examinations. An affected individual (proband) was subjected to whole-exome sequencing (WES). The findings were further validated through Sanger sequencing in the family. Results: Through WES and sanger validation, we identified a novel variant NM_000138.4; c.1402A&gt;G in the Fibrillin-1 (FBN1) gene that segregates with LV diastolic dysfunction and MFS. Furthermore, bioinformatic evaluation suggested that the novel variant is deleterious and disease-causing. Conclusions: This study identified for the first time a novel FBN1 variant in a family with LV diastolic dysfunction and MFS in Pakistan.<\/jats:p>","DOI":"10.3390\/genes12121915","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T05:23:02Z","timestamp":1638163382000},"page":"1915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exome Sequencing Identifies a Novel FBN1 Variant in a Pakistani Family with Marfan Syndrome That Includes Left Ventricle Diastolic Dysfunction"],"prefix":"10.3390","volume":"12","author":[{"given":"Nadia","family":"Farooqi","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University, Mardan 23200, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0530-3524","authenticated-orcid":false,"given":"Louise A.","family":"Metherell","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Charterhouse Square Campus, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Schrauwen","sequence":"additional","affiliation":[{"name":"Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anushree","family":"Acharya","sequence":"additional","affiliation":[{"name":"Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qayum","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University, Mardan 23200, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0378-7788","authenticated-orcid":false,"given":"Liz M.","family":"Nouel Saied","sequence":"additional","affiliation":[{"name":"Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8895-7808","authenticated-orcid":false,"given":"Yasir","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University, Mardan 23200, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7686-0010","authenticated-orcid":false,"given":"Hamed A.","family":"El-Serehy","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh I1451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3372-4457","authenticated-orcid":false,"given":"Fazal","family":"Jalil","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University, Mardan 23200, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne M.","family":"Leal","sequence":"additional","affiliation":[{"name":"Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA"},{"name":"Taub Institute for Alzheimer\u2019s Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,28]]},"reference":[{"key":"ref_1","first-page":"778","article-title":"Cardiomyopathy: An overview","volume":"79","author":"Wexler","year":"2009","journal-title":"Am. Fam. Physician"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1161\/CIRCULATIONAHA.106.174287","article-title":"Contemporary definitions and classification of the cardiomyopathies: An American Heart Association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention","volume":"113","author":"Maron","year":"2006","journal-title":"Circulation"},{"key":"ref_3","unstructured":"Hershberger, R.E., and Jordan, E. (2021, August 02). Dilated Cardiomyopathy Overview, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1309\/pdf\/Bookshelf_NBK1309.pdf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/s41569-019-0284-0","article-title":"Genetics of dilated cardiomyopathy: Practical implications for heart failure management","volume":"17","author":"Rosenbaum","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"102","DOI":"10.15420\/ecr\/2016:19:2","article-title":"Cardiovascular management of adults with Marfan syndrome","volume":"11","author":"Isekame","year":"2016","journal-title":"Eur. Cardiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13073-017-0410-8","article-title":"Genetics and genomics of dilated cardiomyopathy and systolic heart failure","volume":"9","author":"Tayal","year":"2017","journal-title":"Genome Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0140-6736(16)31713-5","article-title":"Dilated cardiomyopathy","volume":"390","author":"Weintraub","year":"2017","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1097\/GIM.0b013e3181f2481f","article-title":"Clinical and genetic issues in dilated cardiomyopathy: A review for genetics professionals","volume":"12","author":"Hershberger","year":"2010","journal-title":"Genet. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.jacc.2012.05.005","article-title":"Where genome meets phenome: Rationale for integrating genetic and protein biomarkers in the diagnosis and management of dilated cardiomyopathy and heart failure","volume":"60","author":"Piran","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/ejhf.1103","article-title":"Evolving concepts in dilated cardiomyopathy","volume":"20","author":"Merlo","year":"2018","journal-title":"Eur. J. Heart Fail."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1056\/NEJMoa1110186","article-title":"Truncations of titin causing dilated cardiomyopathy","volume":"366","author":"Herman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nrcardio.2013.105","article-title":"Dilated cardiomyopathy: The complexity of a diverse genetic architecture","volume":"10","author":"Hershberger","year":"2013","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1016\/S0140-6736(05)67789-6","article-title":"Marfan\u2019s syndrome","volume":"366","author":"Judge","year":"2005","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1002\/humu.22977","article-title":"Marfan syndrome and related disorders: 25 years of gene discovery","volume":"37","author":"Verstraeten","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.amjcard.2004.11.042","article-title":"Evaluation of left ventricular dimensions and function in Marfan\u2019s syndrome without significant valvular regurgitation","volume":"95","author":"Meijboom","year":"2005","journal-title":"Am. J. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/S0002-9149(03)00039-0","article-title":"Left ventricular function in the Marfan syndrome without significant valvular regurgitation","volume":"91","author":"Chatrath","year":"2003","journal-title":"Am. J. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1093\/oxfordjournals.eurheartj.a060558","article-title":"Left ventricular function in children with the Marfan syndrome","volume":"15","author":"Savolainen","year":"1994","journal-title":"Eur. Heart J."},{"key":"ref_18","first-page":"416","article-title":"Diastolic subclinical primary alterations in Marfan syndrome and Marfan-related disorders","volume":"25","author":"Porciani","year":"2002","journal-title":"Clin. Cardiol. Int. Index. Peer-Rev. J. Adv. Treat. Cardiovasc. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.gene.2016.07.033","article-title":"FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders","volume":"591","author":"Sakai","year":"2016","journal-title":"Gene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1096\/fasebj.7.13.8405806","article-title":"Extracellular matrix 4: The elastic fiber","volume":"7","author":"Rosenbloom","year":"1993","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/ejhg.2009.36","article-title":"Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene","volume":"17","author":"Stheneur","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7321","DOI":"10.3892\/mmr.2017.7544","article-title":"A novel FBN1 mutation causes autosomal dominant Marfan syndrome","volume":"16","author":"Xiao","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows\u2013Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows\u2013Wheeler transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature11690","article-title":"Analysis of 6515 exomes reveals the recent origin of most human protein-coding variants","volume":"493","author":"Fu","year":"2013","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Consortium","year":"2015","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/ng.3592","article-title":"Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery","volume":"48","author":"Scott","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13534","DOI":"10.1093\/nar\/gku1206","article-title":"In silico prediction of splice-altering single nucleotide variants in the human genome","volume":"42","author":"Jian","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/humu.22932","article-title":"dbNSFP v3.0: A one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs","volume":"37","author":"Liu","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1093\/bioinformatics\/btm091","article-title":"Enhancements and modifications of primer design program Primer3","volume":"23","author":"Koressaar","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1093\/hmg\/4.suppl_1.1799","article-title":"Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders","volume":"4","author":"Dietz","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/hmg\/ddg081","article-title":"Defective secretion of recombinant fragments of fibrillin-1: Implications of protein misfolding for the pathogenesis of Marfan syndrome and related disorders","volume":"12","author":"Whiteman","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s11033-016-4067-y","article-title":"Novel FBN1 mutations are responsible for cardiovascular manifestations of Marfan syndrome","volume":"43","author":"Yan","year":"2016","journal-title":"Mol. Biol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"55","DOI":"10.2147\/TACG.S96233","article-title":"Marfan syndrome: Current perspectives","volume":"9","author":"Pepe","year":"2016","journal-title":"Appl. Clin. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"32924","DOI":"10.1074\/jbc.M405239200","article-title":"Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1","volume":"279","author":"Vollbrandt","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.gde.2007.04.006","article-title":"Marfan syndrome: From molecular pathogenesis to clinical treatment","volume":"17","author":"Ramirez","year":"2007","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_41","first-page":"7","article-title":"Is ectopia lentis in some cases a mild phenotypic expression of Marfan syndrome? Need for a long-term follow-up","volume":"13","author":"Pepe","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_42","first-page":"1918","article-title":"Identification of a novel FBN1 gene mutation in a large Pakistani family with Marfan syndrome","volume":"18","author":"Micheal","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/ICU.0b013e3282f29f01","article-title":"Pathophysiology of zonular diseases","volume":"19","author":"Dureau","year":"2008","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"34605","DOI":"10.1074\/jbc.M303159200","article-title":"Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by \u03b15\u03b21 and \u03b1v\u03b23 integrins","volume":"278","author":"Bax","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6743","DOI":"10.1074\/jbc.M607008200","article-title":"\u03b1v\u03b26 is a novel receptor for human fibrillin-1: Comparative studies of molecular determinants underlying integrin-RGD affinity and specificity","volume":"282","author":"Takagi","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng1116","article-title":"Dysregulation of TGF-\u03b2 activation contributes to pathogenesis in Marfan syndrome","volume":"33","author":"Neptune","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1083\/jcb.150.3.667","article-title":"New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse","volume":"150","author":"Gayraud","year":"2000","journal-title":"J. Cell Biol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/12\/1915\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:37:01Z","timestamp":1760168221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/12\/1915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,28]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["genes12121915"],"URL":"https:\/\/doi.org\/10.3390\/genes12121915","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2021,11,28]]}}}