AP-HP, Service de génétique moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France.
Université de Paris, INSERM UMR-1141 Neurodiderot, Paris, France.
Prenat Diagn. 2022 May;42(5):601-610. doi: 10.1002/pd.6113. Epub 2022 Feb 20.
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.
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.
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.
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.
COL4A1/COL4A2 基因的变异已在胎儿颅内出血 (ICH) 病例中报道，但在大量胎儿系列中尚未确定其普遍性和特征。胎儿新生儿同种免疫性血小板减少症是获得性 ICH 的主要因素，但导致血小板减少的遗传性血小板疾病 (IPD) 基因变异的普遍性和特征尚不清楚。在此，我们在大量 ICH 胎儿中筛选了 COL4A1/COL4A2 和 IPD 基因。
首先对 194 例连续 ICH 胎儿进行 COL4A1/COL4A2 变异筛查。我们手动整理了 64 个与 IPD 相关的基因列表，并在 101 例 COL4A1/COL4A2 阴性胎儿的外显子组测序数据中对其进行了研究。
在 36 例胎儿 (19%) 中发现了 COL4A1/COL4A2 基因的致病性变异。在有父母 DNA 的 32 例胎儿中，70%的变异是新生的。在两个具有复发性和严重胎儿 ICH 的家族中发现了两个巨核细胞生成基因 (MPL 和 MECOM 基因) 的致病性变异，具有可变的神经外病理特征。
我们的研究强调了胎儿 ICH 的遗传异质性，需要在胎儿 ICH 的病因研究中同时筛查 COL4A1/COL4A2 和 IPD 基因，以提供适当的遗传咨询。
