Details

Autor(en) / Beteiligte

• Coste, Thibault
• Vincent‐Delorme, Catherine
• Stichelbout, Morgane
• Devisme, Louise
• Gelot, Antoinette
• Deryabin, Igor
• Pelluard, Fanny
• Aloui, Chaker
• Leutenegger, Anne‐Louise
• Jouannic, Jean‐Marie
• Héron, Delphine
• Gould, Douglas B
• Tournier‐Lasserve, Elisabeth

Titel

COL4A1/COL4A2 and inherited platelet disorder gene variants in fetuses showing intracranial hemorrhage

Ist Teil von

• Prenatal diagnosis, 2022-05, Vol.42 (5), p.601-610

Ort / Verlag

England: Wiley Subscription Services, Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Background Variants of COL4A1/COL4A2 genes have been reported in fetal intracranial hemorrhage (ICH) cases but their prevalence and characteristics have not been established in a large series of fetuses. Fetal neonatal alloimmune thrombocytopenia is a major acquired ICH factor but the prevalence and characteristics of inherited platelet disorder (IPD) gene variants leading to thrombocytopenia are unknown. Herein, we screened COL4A1/COL4A2 and IPD genes in a large series of ICH fetuses. Methods A cohort of 194 consecutive ICH fetuses were first screened for COL4A1/COL4A2 variants. We manually curated a list of 64 genes involved in IPD and investigated them in COL4A1/COL4A2 negative fetuses, using exome sequencing data from 101 of these fetuses. Result Pathogenic variants of COL4A1/COL4A2 genes were identified in 36 fetuses (19%). They occurred de novo in 70% of the 32 fetuses for whom parental DNA was available. Pathogenic variants in two megakaryopoiesis genes (MPL and MECOM genes) were identified in two families with recurrent and severe fetal ICH, with variable extraneurological pathological features. Conclusion Our study emphasizes the genetic heterogeneity of fetal ICH and the need to screen both COL4A1/COL4A2 and IPD genes in the etiological investigation of fetal ICH to allow proper genetic counseling. Key points What's already known about this topic? COL4A1/COL4A2 pathogenic variants have been reported in several fetal intracranial hemorrhage (ICH) case reports but their prevalence and characteristics in a large series of fetal ICH is lacking. Fetal neonatal alloimmune thrombocytopeniais a well‐known cause of thrombocytopenia and ICH in infants and fetuses but very little is known regarding the role in fetal ICH of variants of inherited platelet disorder genes leading to thrombocytopenia. What does this study add? Fetal ICH is a highly heterogeneous condition with COL4A1/COL4A2 pathogenic variants accounting for 19% of cases with a very high de novo rate. Albeit rare, pathogenic variants of megakaryopoiesis genes are associated with ICH and screening of these genes should be performed in fetal ICH etiological investigation.