Exome Sequencing of Fetuses With Intracranial Hemorrhage Unravels Novel Causative Genes and an Extreme Genetic Heterogeneity

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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.

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