{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:26:14Z","timestamp":1790774774139,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T00:00:00Z","timestamp":1589846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100013302","name":"King Abdullah International Medical Research Center","doi-asserted-by":"publisher","award":["RC15\/140"],"award-info":[{"award-number":["RC15\/140"]}],"id":[{"id":"10.13039\/501100013302","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recently, <jats:italic>ADAMTS19<\/jats:italic> was identified as a novel causative gene for autosomal recessive heart valve disease (HVD), affecting mainly the aortic and pulmonary valves. Exome sequencing and data repository (CentoMD) analyses were performed to identify patients with <jats:italic>ADAMTS19<\/jats:italic> variants (two families). A third family was recognized based on cardiac phenotypic similarities and SNP array homozygosity. Three novel loss of function (LoF) variants were identified in six patients from three families. Clinically, all patients presented anomalies of the aortic\/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. Three patients had (recurrent) subaortic membrane, suggesting that <jats:italic>ADAMTS19<\/jats:italic> is the first gene identified related to discrete subaortic stenosis. One case presented a bi\u2010commissural pulmonary valve. All patients displayed some degree of atrioventricular valve insufficiency. Other cardiac anomalies included atrial\/ventricular septal defects, persistent ductus arteriosus, and mild dilated ascending aorta. Our findings confirm that biallelic LoF variants in <jats:italic>ADAMTS19<\/jats:italic> are causative of a specific and recognizable cardiac phenotype. We recommend considering <jats:italic>ADAMTS19<\/jats:italic> genetic testing in all patients with multiple semilunar valve abnormalities, particularly in the presence of subaortic membrane. <jats:italic>ADAMTS19<\/jats:italic> screening in patients with semilunar valve abnormalities is needed to estimate the frequency of the HVD related phenotype, which might be not so rare.<\/jats:p>","DOI":"10.1111\/cge.13760","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T08:52:17Z","timestamp":1587631937000},"page":"56-63","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<scp><i>ADAMTS19<\/i><\/scp>\u2010associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype"],"prefix":"10.1111","volume":"98","author":[{"given":"Salam","family":"Massadeh","sequence":"first","affiliation":[{"name":"Department of Developmental Medicine, King Abdullah International Medical Research Center King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs  Riyadh Saudi Arabia"},{"name":"The Joint Center of Excellence for Biomedicine Between King Abdulaziz City for Science and Technology (KACST) and Brigham &amp; Women's Hospital (BWH) Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Alhashem","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics, Department of Pediatrics Prince Sultan Military Medical City  Riyadh Saudi Arabia"},{"name":"Department of Anatomy and Cell biology College of Medicine, Alfaisal University  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2523-1230","authenticated-orcid":false,"given":"Ingrid M.B.H.","family":"van de Laar","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahad","family":"Alhabshan","sequence":"additional","affiliation":[{"name":"Department of Cardiac Sciences, Ministry of the National Guard\u2014Health Affairs, King Abdullah International Medical Research Center King Saud bin Abdulaziz University for Health Sciences  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Ordonez","sequence":"additional","affiliation":[{"name":"CENTOGENE AG  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salem","family":"Alawbathani","sequence":"additional","affiliation":[{"name":"CENTOGENE AG  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suliman","family":"Khan","sequence":"additional","affiliation":[{"name":"CENTOGENE AG  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Kabbani","sequence":"additional","affiliation":[{"name":"Department of Cardiac Sciences, Ministry of the National Guard\u2014Health Affairs, King Abdullah International Medical Research Center King Saud bin Abdulaziz University for Health Sciences  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Chaikhouni","sequence":"additional","affiliation":[{"name":"Department of Cardiac Sciences, Ministry of the National Guard\u2014Health Affairs, King Abdullah International Medical Research Center King Saud bin Abdulaziz University for Health Sciences  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atia","family":"Sheereen","sequence":"additional","affiliation":[{"name":"Department of Developmental Medicine, King Abdullah International Medical Research Center King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Almohammed","sequence":"additional","affiliation":[{"name":"Department of Developmental Medicine, King Abdullah International Medical Research Center King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs  Riyadh Saudi Arabia"},{"name":"The Joint Center of Excellence for Biomedicine Between King Abdulaziz City for Science and Technology (KACST) and Brigham &amp; Women's Hospital (BWH) Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bader","family":"Alghamdi","sequence":"additional","affiliation":[{"name":"Department of Developmental Medicine, King Abdullah International Medical Research Center King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Frohn\u2010Mulder","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Prince Sultan Cardiac Center, Prince Sultan Military Medical City  Riyad Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7061-2895","authenticated-orcid":false,"given":"Christian","family":"Beetz","sequence":"additional","affiliation":[{"name":"CENTOGENE AG  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9414-4555","authenticated-orcid":false,"given":"Peter","family":"Bauer","sequence":"additional","affiliation":[{"name":"CENTOGENE AG  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja W.","family":"Wessels","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal","family":"Alaamery","sequence":"additional","affiliation":[{"name":"Department of Developmental Medicine, King Abdullah International Medical Research Center King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs  Riyadh Saudi Arabia"},{"name":"The Joint Center of Excellence for Biomedicine Between King Abdulaziz City for Science and Technology (KACST) and Brigham &amp; Women's Hospital (BWH) Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9544-1877","authenticated-orcid":false,"given":"Aida M.","family":"Bertoli\u2010Avella","sequence":"additional","affiliation":[{"name":"CENTOGENE AG  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,5,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr062"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/heart.89.7.806"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.08.025"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)01886-7"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.1286"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01827"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03940"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22030"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-019-0363-z"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0536-2"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2016.146"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0016-6"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.262"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1754"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1113"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2018.00122"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.07.013"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2006.08.034"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/clc.4960210113"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2007.01.095"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.193"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313737"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2015.03.001"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3970"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-018-1457-6"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2010.01.005"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.313077"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcge.13760","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.13760","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.13760","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.13760","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T08:34:33Z","timestamp":1693730073000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.13760"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,19]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,7]]}},"alternative-id":["10.1111\/cge.13760"],"URL":"https:\/\/doi.org\/10.1111\/cge.13760","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,19]]},"assertion":[{"value":"2020-03-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}