{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T22:37:15Z","timestamp":1793659035145,"version":"4.5.1"},"reference-count":54,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS096173"],"award-info":[{"award-number":["R01NS096173"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002738","name":"Assistance Publique - H\u00f4pitaux de Paris","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["obgyn.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Prenatal Diagnosis"],"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Fetal intracranial hemorrhage (FICH) is a rare and potentially deleterious condition. Fetal alloimmune thrombocytopenia and pathogenic variations in <jats:italic>COL4A1\/A2<\/jats:italic> genes are well\u2010recognized causes of FICH. However, pathogenic <jats:italic>COL4A1\/A2<\/jats:italic> variations are identified in only 20% of fetuses referred for FICH after excluding other known causes, leaving the majority unexplained and making genetic counseling difficult. Our main aim was to identify novel genes associated with FICH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Exome sequencing was performed on 113 unrelated fetuses (35 trios, 3 families and 75 probands) after negative <jats:italic>COL4A1\/A2<\/jats:italic> testing and exclusion of known risk factors. Exome analysis incorporated several strategies including analyses of <jats:italic>de novo<\/jats:italic> and biallelic variants, and a collapsing gene\u2010based burden test approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nine individuals (8%) had a pathogenic or likely pathogenic variant identified. Additionally, 14 fetuses had a suspicious variant identified in a candidate gene. Causative genes involved platelet production, hemostasis (<jats:italic>MPL, MECOM, PROC<\/jats:italic>), endothelial cell adhesion (<jats:italic>ESAM<\/jats:italic>), and mitochondrial metabolism (<jats:italic>ATP5PO, COQ2, PDHA1<\/jats:italic>). These findings suggest that FICH may result from a broader range of genetic abnormalities beyond previously known C<jats:italic>OL4A1\/A2<\/jats:italic> gene mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>FICH is characterized by extreme genetic heterogeneity with various pathways involved, underscoring the importance of exome\u2010wide analyses to fully understand its causes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pd.6743","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T06:23:23Z","timestamp":1736231003000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exome Sequencing of Fetuses With Intracranial Hemorrhage Unravels Novel Causative Genes and an Extreme Genetic Heterogeneity"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5610-7411","authenticated-orcid":false,"given":"Thibault","family":"Coste","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 Inserm NeuroDiderot  Paris France"},{"name":"Service de G\u00e9n\u00e9tique Neurovasculaire AP\u2010HP H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaker","family":"Aloui","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 Inserm NeuroDiderot  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Chanclud","sequence":"additional","affiliation":[{"name":"Department of Pediatric Radiology Trousseau Hospital AP\u2010HP  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u00e9onore","family":"Blondiaux","sequence":"additional","affiliation":[{"name":"Department of Pediatric Radiology Trousseau Hospital AP\u2010HP  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4595-7271","authenticated-orcid":false,"given":"Jelena","family":"Martinovic","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de F\u0153topathologie AP\u2010HP H\u00f4pital Antoine B\u00e9cl\u00e8re Groupe Hospitalo\u2010Universitaire Paris Saclay  Clamart France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Attie\u2010Bitach","sequence":"additional","affiliation":[{"name":"Service de M\u00e9decine G\u00e9nomique des Maladies Rares H\u00f4pital Universitaire Necker\u2010Enfants Malades  Paris France"},{"name":"INSERM UMR 1163 Institut Imagine Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Petit","sequence":"additional","affiliation":[{"name":"Univ. Lille Clinique de G\u00e9n\u00e9tique Guy Fontaine  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"H\u00e9ron","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique M\u00e9dicale Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re AP\u2010HP Sorbonne Universit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre G.","family":"de Brevern","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 and Universit\u00e9 de la R\u00e9union INSERM UMR_S 1134 DSIMB Bioinformatics Team GR\u2010Ex  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragousandirane","family":"Radjasandirane","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 and Universit\u00e9 de la R\u00e9union INSERM UMR_S 1134 DSIMB Bioinformatics Team GR\u2010Ex  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaelle","family":"Corpechot","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique Neurovasculaire AP\u2010HP H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Morel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 Inserm NeuroDiderot  Paris France"},{"name":"Service de G\u00e9n\u00e9tique Neurovasculaire AP\u2010HP H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Petermann","sequence":"additional","affiliation":[{"name":"Platelets Immunology Laboratory National Reference Centre for Perinatal Hemobiology (CNRHP)  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Louise","family":"Leutenegger","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 Inserm NeuroDiderot  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Tournier\u2010Lasserve","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 Inserm NeuroDiderot  Paris France"},{"name":"Service de G\u00e9n\u00e9tique Neurovasculaire AP\u2010HP H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2020.08.183"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.14713"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/14767058.2017.1369521"},{"issue":"2","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ajog.2021.04.211","article-title":"New Developments in Fetal and Neonatal Alloimmune Thrombocytopenia","volume":"225","author":"Bussel J. 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