Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation
Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation
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DOI：
10.1016/j.neuron.2018.11.041
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发表时间：
2019-02-06
期刊：
影响因子：
16.2
通讯作者：
Kahle, Kristopher T.
中科院分区：
文献类型：
--
作者：
Duran, Daniel;Zeng, Xue;Kahle, Kristopher T.
正常的血管发育包括动脉、静脉和介入毛细血管的形成和规范。盖伦静脉畸形 (VOGM) 是最常见和最严重的新生儿脑动静脉畸形之一，它通过异常的直接连接将动脉血分流到大脑的深静脉系统。对 55 名 VOGM 先证者（包括 52 名亲子三人组）的外显子组测序揭示了染色质修饰基因中罕见的破坏性从头突变的富集，这些基因在大脑和血管发育中发挥着重要作用。其他 VOGM 先证者在 Ephrin 信号基因中携带罕见的遗传性破坏性突变，包括 EPHB4 的全基因组显着突变负担。遗传性突变表现出不完全的外显率和可变的表达性，突变携带者经常表现出皮肤血管异常，表明存在二次打击机制。所识别的突变总共占研究 VOGM 病例的 30%。这些发现提供了对疾病生物学的深入了解，并可能对风险评估具有临床意义。
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for similar to 30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.