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 C OL4A1/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.