Diffuse angiopathy in Adams-Oliver syndrome associated with truncating DOCK6 mutations.
Diffuse angiopathy in Adams-Oliver syndrome associated with truncating DOCK6 mutations.
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DOI：
10.1002/ajmg.a.36685
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发表时间：
2014-10
影响因子：
2
通讯作者：
Patel, Millan
中科院分区：
文献类型：
--
作者：
Lehman, Anna;Stittrich, Anna-Barbara;Glusman, Gustavo;Zong, Zheyuan;Li, Hong;Eydoux, Patrice;Senger, Christof;Lyons, Christopher;Roach, Jared C.;Patel, Millan
关键词：
Adams-Oliver综合征（AOS）是一种罕见的畸形综合征，其特征在于存在两种异常：头皮先天性皮肤发育不全和横向末端肢体缺损。许多受影响的个体还具有其他畸形，包括各种颅内异常，如与脑血管微出血一致的脑室周围钙化、神经元迁移受损、癫痫和小头畸形。可能存在心脏畸形，也可能存在血管功能障碍，表现为先天性大理石状皮肤毛细血管扩张、肺静脉狭窄和肝脏微血管异常。阐明的遗传原因包括四个基因在不同的途径，导致AOS作为一个多途径疾病的模型。我们确定了一个婴儿轻度先天性皮肤发育不全和终端横向肢体缺陷，发育迟缓和严重的，弥漫性血管病与不完全微血管化。全基因组测序记录了DOCK 6中两种罕见的截短变体，DOCK 6是一种与常染色体隐性AOS相关的基因，其复发特征为脑室周围钙化和神经发育受损。我们强调了一个意想不到的高频率的可能有害的突变，在这个基因在一般人群中，相对于罕见的疾病，并讨论了这种差异的可能解释。
Adams-Oliver syndrome (AOS) is a rare malformation syndrome characterized by the presence of two anomalies: aplasia cutis congenita of the scalp and transverse terminal limb defects. Many affected individuals also have additional malformations, including a variety of intracranial anomalies such as periventricular calcification in keeping with cerebrovascular microbleeds, impaired neuronal migration, epilepsy, and microcephaly. Cardiac malformations can be present, as can vascular dysfunction in the forms of cutis marmorata telangiectasia congenita, pulmonary vein stenoses, and abnormal hepatic microvasculature. Elucidated genetic causes include four genes in different pathways, leading to a model of AOS as a multi-pathway disorder. We identified an infant with mild aplasia cutis congenita and terminal transverse limb defects, developmental delay and a severe, diffuse angiopathy with incomplete microvascularization. Whole-genome sequencing documented two rare truncating variants in DOCK6, a gene associated with a type of autosomal recessive AOS that recurrently features periventricular calcification and impaired neurodevelopment. We highlight an unexpectedly high frequency of likely deleterious mutations in this gene in the general population, relative to the rarity of the disease, and discuss possible explanations for this discrepancy.
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