{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T07:23:13Z","timestamp":1763018593384,"version":"3.41.2"},"reference-count":10,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Patients with a univentricular heart form a morphological heterogenous group of patients at the most severe end of the congenital heart disease (CHD) spectrum. Over the past decades, more awareness and knowledge has been raised on the genetic contributions to CHD. To date, only a limited number of genes have been identified in the hypoplastic heart, mainly in left-sided hypoplasia. There is still much more to be elucidated in this field.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Case summary<\/jats:title>\n                  <jats:p>Here, we present a follow-up report of a case of an adult patient after Fontan palliation, born with a.o. tricuspid atresia with hypoplastic right ventricle and pulmonary stenosis. This patient encountered a myriad of late sequalae involving multiple organ systems during the course of his young adult life, including refractory protein losing enteropathy (PLE). Concomitant extracardiac anomalies, in addition to the complex CHD and its complications, prompted for genetic evaluation. Whole exome sequencing showed a variant of uncertain significance in the BRAF gene [NM_004333.4:c.1897T &amp;gt; C p.(Tyr633His)], associated with Noonan spectrum disorders, that is also infamous for lymphoedema and PLE. The variant regards an evolutionarily highly conserved amino acid and is assumed pathogenic according to all prediction programmes. The mutation was most likely de novo.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>Genetic screening can provide new insights in the complex and varied phenotype of the (adult) Fontan patient and in the myriad of complications encountered. Adult CHD cardiologists should be aware of genetic syndromes underlying a CHD, concomitant extracardiac anomalies, and a complex clinical course with a broad spectrum of late sequelae.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ehjcr\/ytad176","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T11:45:40Z","timestamp":1680781540000},"source":"Crossref","is-referenced-by-count":1,"title":["Genetic variant in the <i>BRAF<\/i> gene compatible with Noonan spectrum disorders in an adult Fontan patient with refractory protein losing enteropathy: a follow-up report"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4893-6575","authenticated-orcid":false,"given":"Marieke","family":"Nederend","sequence":"first","affiliation":[{"name":"CAHAL, Center for Congenital Heart Disease Amsterdam Leiden, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"},{"name":"Department of Cardiology, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J Lauran","family":"Stoger","sequence":"additional","affiliation":[{"name":"Department of Radiology, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia D","family":"Egorova","sequence":"additional","affiliation":[{"name":"CAHAL, Center for Congenital Heart Disease Amsterdam Leiden, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"},{"name":"Department of Cardiology, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4461-4293","authenticated-orcid":false,"given":"Daniela Q C M","family":"Barge-Schaapveld","sequence":"additional","affiliation":[{"name":"CAHAL, Center for Congenital Heart Disease Amsterdam Leiden, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"},{"name":"Department of Clinical Genetics, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9132-0418","authenticated-orcid":false,"given":"Monique R M","family":"Jongbloed","sequence":"additional","affiliation":[{"name":"CAHAL, Center for Congenital Heart Disease Amsterdam Leiden, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"},{"name":"Department of Cardiology, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"},{"name":"Department of Anatomy and Embryology, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"2023042815550890200_ytad176-B1","doi-asserted-by":"crossref","first-page":"ytac067","DOI":"10.1093\/ehjcr\/ytac067","article-title":"Case report of the broad spectrum of late complications in an adult patient with univentricular physiology palliated by the Fontan circulation","volume":"6","author":"Nederend","year":"2022","journal-title":"Eur Heart J Case Rep"},{"key":"2023042815550890200_ytad176-B2","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"2023042815550890200_ytad176-B3","doi-asserted-by":"crossref","first-page":"e653","DOI":"10.1161\/CIR.0000000000000606","article-title":"Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association","volume":"138","author":"Pierpont","year":"2018","journal-title":"Circulation"},{"key":"2023042815550890200_ytad176-B4","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1002\/joa3.12717","article-title":"European Heart Rhythm Association (EHRA)\/Heart Rhythm Society (HRS)\/Asia Pacific Heart Rhythm Society (APHRS)\/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases","volume":"38","author":"Wilde","year":"2022","journal-title":"J Arrhythm"},{"key":"2023042815550890200_ytad176-B5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S1556-0864(15)31506-9","article-title":"The Ras\/Raf\/MAPK pathway","volume":"1","author":"Molina","year":"2006","journal-title":"J Thorac 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Javier","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]},{"given":"David","family":"Blusztein","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]},{"given":"Luis Antonio","family":"Moreno-Ruiz","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,4,1]]},"references-count":10,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4,10]]}},"URL":"https:\/\/doi.org\/10.1093\/ehjcr\/ytad176","relation":{},"ISSN":["2514-2119"],"issn-type":[{"type":"electronic","value":"2514-2119"}],"subject":[],"published-other":{"date-parts":[[2023,4,1]]},"published":{"date-parts":[[2023,4,1]]},"article-number":"ytad176"}}