{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:16:11Z","timestamp":1778624171931,"version":"3.51.4"},"reference-count":74,"publisher":"The Royal Society","issue":"1710","license":[{"start":{"date-parts":[[2016,12,19]],"date-time":"2016-12-19T00:00:00Z","timestamp":1482105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"funder":[{"DOI":"10.13039\/100000912","name":"March of Dimes Foundation","doi-asserted-by":"publisher","award":["#1FY10-401"],"award-info":[{"award-number":["#1FY10-401"]}],"id":[{"id":"10.13039\/100000912","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["#1008496"],"award-info":[{"award-number":["#1008496"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Phil. Trans. R. Soc. B"],"published-print":{"date-parts":[[2016,12,19]]},"abstract":"<jats:p>\n                    Genomic disorders and rare copy number abnormalities are identified in 15\u201325% of patients with syndromic conditions, but their prevalence in individuals with isolated birth defects is less clear. A spectrum of congenital heart defects (CHDs) is seen in heterotaxy, a highly heritable and genetically heterogeneous multiple congenital anomaly syndrome resulting from failure to properly establish left\u2013right (L-R) organ asymmetry during early embryonic development. To identify novel genetic causes of heterotaxy, we analysed copy number variants (CNVs) in 225 patients with heterotaxy and heterotaxy-spectrum CHDs using array-based genotyping methods. Clinically relevant CNVs were identified in approximately 20% of patients and encompassed both known and putative heterotaxy genes. Patients were carefully phenotyped, revealing a significant association of abdominal situs inversus with pathogenic or likely pathogenic CNVs, while d-transposition of the great arteries was more frequently associated with common CNVs. Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in\n                    <jats:italic>ZIC3,<\/jats:italic>\n                    a gene known to cause X-linked heterotaxy. Morpholino loss-of-function experiments in\n                    <jats:italic>Xenopus<\/jats:italic>\n                    support a role for one of these novel candidates, the platelet isoform of phosphofructokinase-1 (\n                    <jats:italic>PFKP<\/jats:italic>\n                    ) in heterotaxy. Collectively, our results confirm a high CNV yield for array-based testing in patients with heterotaxy, and support use of CNV analysis for identification of novel biological processes relevant to human laterality.\n                  <\/jats:p>\n                  <jats:p>This article is part of the themed issue \u2018Provocative questions in left\u2013right asymmetry\u2019.<\/jats:p>","DOI":"10.1098\/rstb.2015.0406","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T20:54:07Z","timestamp":1478552047000},"page":"20150406","update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects"],"prefix":"10.1098","volume":"371","author":[{"given":"Jason R.","family":"Cowan","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics and Medical and Molecular Genetics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Tariq","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medical and Molecular Genetics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Department of Clinical Biochemistry, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chad","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John W.","family":"Belmont","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seema R.","family":"Lalani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa A.","family":"Smolarek","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center, Division of Human Genetics, Cincinnati, OH 45229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie M.","family":"Ware","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medical and Molecular Genetics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2016,12,19]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00125817-200005000-00002"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36695"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2007.12.032"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2010.07.082"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.07.053"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.857987"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201506"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22457"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1086\/380998"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt001"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn411"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.05.012"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-102209-163544"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.9.081307.164217"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40142-014-0049-3"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019645108"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.112"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3871"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21360"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2012.01.011"},{"key":"e_1_3_6_22_2","volume-title":"Normal table of Xenopus laevis","author":"Nieuwkoop P","year":"1994"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2000.9720"},{"key":"e_1_3_6_24_2","volume-title":"Early development of Xenopus laevis: a laboratory manual. 2000","author":"Sive HL","year":"2000"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp233"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01663"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81705-5"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.10.067"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002010309"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2009.05.547"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.21855"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.90258.2008"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210077200"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02341"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2000.9739"},{"key":"e_1_3_6_36_2","first-page":"53","article-title":"Changes in activity of the regulatory glycolytic enzymes and of the pyruvate-dehydrogenase complex during the development of Xenopus laevis","volume":"54","author":"Raddatz E","year":"1986","journal-title":"Exp. Cell Biol"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/0968-0004(91)90091-9"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2140703"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2010.02.061"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2014.06.014"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30228"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.649038"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.13-1704"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.105"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21337"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.756"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201006105"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e12-02-0134"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.1086\/519026"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.10.010"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.03842"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diff.2011.11.003"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600307"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.008599"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2002.0716"},{"key":"e_1_3_6_56_2","first-page":"2063","article-title":"ACVR1, a therapeutic target of fibrodysplasia ossificans progressiva, is negatively regulated by miR-148a","volume":"13","author":"Song H","year":"2012","journal-title":"AAPG Bull"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.330381"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990101)82:1<70::AID-AJMG14>3.0.CO;2-Y"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.909"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.08.003"},{"key":"e_1_3_6_61_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2011.01637.x"},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu144"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119831"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00059-010-3244-3"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gep.2013.04.002"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-198011000-00003"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22450"},{"key":"e_1_3_6_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6953"},{"key":"e_1_3_6_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.08.002"},{"key":"e_1_3_6_70_2","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.02014"},{"key":"e_1_3_6_71_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/675430"},{"key":"e_1_3_6_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.09.001"},{"key":"e_1_3_6_73_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1235587"},{"key":"e_1_3_6_74_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1222794"},{"key":"e_1_3_6_75_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1225057"}],"container-title":["Philosophical Transactions of the Royal Society B: Biological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.2015.0406","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/full-xml\/10.1098\/rstb.2015.0406","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.2015.0406","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:21:52Z","timestamp":1778620912000},"score":1,"resource":{"primary":{"URL":"http:\/\/royalsocietypublishing.org\/rstb\/article\/23085"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,19]]},"references-count":74,"journal-issue":{"issue":"1710","published-print":{"date-parts":[[2016,12,19]]}},"alternative-id":["10.1098\/rstb.2015.0406"],"URL":"https:\/\/doi.org\/10.1098\/rstb.2015.0406","relation":{},"ISSN":["0962-8436","1471-2970"],"issn-type":[{"value":"0962-8436","type":"print"},{"value":"1471-2970","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,19]]},"assertion":[{"value":"2016-06-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-12-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}