Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.

中文翻译：

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与异常信号传导相关的 EPHB4 SAM 结构域变异与淋巴相关的胎儿水肿和面部畸形有关

EPHB4（肝配蛋白 B 型受体 4）是一种跨膜酪氨酸激酶受体，已在患有各种血管异常的个体中发现变异，包括毛细血管畸形-动静脉畸形综合征 2 和淋巴相关（非免疫）胎儿水肿 (LRHF)。在这里，我们鉴定了EPHB4中的两个新变体，它们破坏了两个不相关个体的 SAM 结构域。先证者 1 在 LRHF 表型谱中表现为水肿，先证者 2 在产前表现为大颈项半透明，除了产后检查中的畸形特征外，该现象自发消退。这些是第一个被鉴定的与疾病相关的变体，它们不会破坏 EPHB4 蛋白表达或酪氨酸激酶活性。我们发现 EPHB4 SAM 结构域破坏会导致下游信号传导异常，SAM 结构域的缺失会导致先证者 1 中的 MAPK 信号传导升高，而 SAM 结构域内的错义变异会导致先证者 2 中的细胞增殖增加。该数据强调正常的 EPHB4 功能和血管发育需要功能性 SAM 结构域。