{"doi":"10.1002/pd.6743","title":"Exome Sequencing of Fetuses With Intracranial Hemorrhage Unravels Novel Causative Genes and an Extreme Genetic Heterogeneity","abstract":"OBJECTIVE: Fetal intracranial hemorrhage (FICH) is a rare and potentially deleterious condition. Fetal alloimmune thrombocytopenia and pathogenic variations in COL4A1/A2 genes are well-recognized causes of FICH. However, pathogenic COL4A1/A2 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. METHOD: Exome sequencing was performed on 113 unrelated fetuses (35 trios, 3 families and 75 probands) after negative COL4A1/A2 testing and exclusion of known risk factors. Exome analysis incorporated several strategies including analyses of de novo and biallelic variants, and a collapsing gene-based burden test approach. RESULTS: 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 (MPL, MECOM, PROC), endothelial cell adhesion (ESAM), and mitochondrial metabolism (ATP5PO, COQ2, PDHA1). These findings suggest that FICH may result from a broader range of genetic abnormalities beyond previously known COL4A1/A2 gene mutations. CONCLUSION: FICH is characterized by extreme genetic heterogeneity with various pathways involved, underscoring the importance of exome-wide analyses to fully understand its causes.","journal":"Prenatal Diagnosis","year":2025,"id":549930,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":896414,"name":"Chaker Aloui","orcid":"0000-0002-0914-5260","position":1,"is_corresponding":false},{"id":1445326,"name":"Justine Chanclud","orcid":null,"position":2,"is_corresponding":false},{"id":1149088,"name":"Éléonore Blondiaux","orcid":"0000-0002-2594-5428","position":3,"is_corresponding":false},{"id":901007,"name":"Jéléna Martinovic","orcid":"0000-0003-4595-7271","position":4,"is_corresponding":false},{"id":900998,"name":"Tania Attié‐Bitach","orcid":"0000-0002-1155-3626","position":5,"is_corresponding":false},{"id":247596,"name":"Florence Petit","orcid":"0000-0002-1368-1023","position":6,"is_corresponding":false},{"id":274394,"name":"Delphine Héron","orcid":"0000-0002-1627-7958","position":7,"is_corresponding":false},{"id":1444595,"name":"Alexandre G. de Brevern","orcid":"0000-0001-7112-5626","position":8,"is_corresponding":false},{"id":1444596,"name":"Ragousandirane Radjasandirane","orcid":"0000-0002-6311-6794","position":9,"is_corresponding":false},{"id":1168060,"name":"Michaelle Corpechot","orcid":null,"position":10,"is_corresponding":false},{"id":1445327,"name":"Hélène Morel","orcid":null,"position":11,"is_corresponding":false},{"id":1444597,"name":"Rachel Petermann","orcid":"0000-0002-2082-6278","position":12,"is_corresponding":false},{"id":896415,"name":"Anne‐Louise Leutenegger","orcid":"0000-0002-1302-4357","position":13,"is_corresponding":false},{"id":673955,"name":"Elisabeth Tournier‐Lasserve","orcid":"0000-0002-3039-1677","position":14,"is_corresponding":false},{"id":896412,"name":"Thibault Coste","orcid":"0000-0001-5610-7411","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:54:12.321988Z","pmid":"39763161","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}