Delineation of phenotypes and genotypes related to cohesin structural protein RAD21
Delineation of phenotypes and genotypes related to cohesin structural protein RAD21
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DOI：
10.1007/s00439-020-02138-2
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发表时间：
2020-03-19
期刊：
影响因子：
5.3
通讯作者：
Hennekam, Raoul C.
中科院分区：
文献类型：
--
作者：
Krab, Lianne C.;Marcos-Alcalde, Inigo;Hennekam, Raoul C.
RAD21编码内聚蛋白复合物的一个关键成分，RAD21的变异与Cornelia de Lange综合征（CdLS）有关。目前发表的有关RAD21变异的表型和基因型-表型关系的信息有限。我们收集了来自33个家族的49个RAD21突变个体[24个不同的基因内序列变异（2个复发），7个独特的微缺失]，包括24个迄今未发表的病例。我们通过蛋白质模型和分子动力学研究评估了12种基因内变异的后果。有29人的完整临床信息。与NIPBL或SMC1A变异引起的面部形态、肢体异常，特别是认知和行为的CdLS表型相比，它们的表型是一种减弱的CdLS表型。在临床信息有限的20个个体中，其他表型包括Mungan综合征（双等位基因变异患者）和前脑畸形，具有或不具有CdLS特征。我们描述了其他几种包括硬角膜在内的表型病例，其中RAD21变异的参与尚不确定。变异通常是家族性的，基因型-表型分析显示了显著的家族间和家族内变异性。在解释RAD21变异的后果时，仔细的表型分析是必不可少的，蛋白质建模和动力学可以帮助确定致病性。目前的研究应该对RAD21变异家庭的咨询有所帮助。
RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.