{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:27:11Z","timestamp":1788920831619,"version":"build-2803163510"},"reference-count":41,"publisher":"American Physiological Society","issue":"12","funder":[{"name":"A Healthier Wisconsin CVC Pilot Award","award":["5520361"],"award-info":[{"award-number":["5520361"]}]},{"name":"Wanek Consortium for HLHS"},{"name":"Wolfe Family Foundation"},{"name":"Little Hearts for Life"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiological Genomics"],"published-print":{"date-parts":[[2016,12,1]]},"abstract":"<jats:p> Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD\/HLHS, identifying a rare variant in the \u03b1-myosin heavy chain ( MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases ( P &lt; 1 \u00d7 10<jats:sup>\u22125<\/jats:sup>). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants ( P &lt; 1 \u00d7 10<jats:sup>\u22122<\/jats:sup>). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the \u03b2-myosin heavy chain ( MYH7) gene in subjects with MYH6 variants ( P &lt; 1 \u00d7 10<jats:sup>\u22123<\/jats:sup>). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo ( P &lt; 1 \u00d7 10<jats:sup>\u22122<\/jats:sup>), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications. <\/jats:p>","DOI":"10.1152\/physiolgenomics.00091.2016","type":"journal-article","created":{"date-parts":[[2016,10,28]],"date-time":"2016-10-28T02:53:51Z","timestamp":1477623231000},"page":"912-921","source":"Crossref","is-referenced-by-count":86,"title":["Impact of <i>MYH6<\/i> variants in hypoplastic left heart syndrome"],"prefix":"10.1152","volume":"48","author":[{"given":"Aoy","family":"Tomita-Mitchell","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl D.","family":"Stamm","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"},{"name":"Department of Mathematics, Statistics and Computer Science, Marquette University, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna K.","family":"Mahnke","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Su","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pip M.","family":"Hidestrand","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Eastern Maine Medical Center, Bangor, Maine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan Ling","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary A.","family":"Goetsch","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Hidestrand","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pippa","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Pelech","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Heart Center, UC Davis Children's Hospital, Sacramento, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Tweddell","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, the Heart Institute, Cincinnati Children's Hospital, Cincinnati, Ohio;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Woodrow","family":"Benson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Lough","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.111.961797"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00838"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.19.2376"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.507699"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.2.1252"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ng1526"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0027-5107(01)00160-9"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000266606.88463.cb"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.94.9.2285"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(03)00420-0"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nature03940"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq315"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000268192.20525.c2"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.12.024"},{"key":"B15","first-page":"24","volume":"38","author":"Harris S","year":"2011","journal-title":"J Registry Manag"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.07.021"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.12.023"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nature01282"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu186"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1353-x"},{"key":"B21","doi-asserted-by":"crossref","first-page":"e0118670","DOI":"10.1371\/journal.pone.0118670","volume":"10","author":"Kim MS","year":"2015","journal-title":"PLoS One"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.12.5251"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2003-0782-L"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(200024)97:4<319::AID-AJMG1283>3.0.CO;2-E"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012630"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119770"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nature13127"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.1200113"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn187"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.4.386"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.09.029"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-3955(16)30727-1"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028872"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.280.4.H1814"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.05100.x"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951106000291"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.115.001070"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00013.2012"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/ng.922"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1353-9"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.513291"}],"container-title":["Physiological Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/physiolgenomics.00091.2016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T23:38:01Z","timestamp":1567985881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/physiolgenomics.00091.2016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,1]]},"references-count":41,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016,12,1]]}},"alternative-id":["10.1152\/physiolgenomics.00091.2016"],"URL":"https:\/\/doi.org\/10.1152\/physiolgenomics.00091.2016","relation":{},"ISSN":["1094-8341","1531-2267"],"issn-type":[{"value":"1094-8341","type":"print"},{"value":"1531-2267","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,1]]}}}