Phenotypes and genotypes in individuals with SMC1A variants
Phenotypes and genotypes in individuals with SMC1A variants
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DOI：
10.1002/ajmg.a.38279
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发表时间：
2017-08-01
影响因子：
2
通讯作者：
Hennekam, Raoul C.
中科院分区：
文献类型：
--
作者：
Huisman, Sylvia;Mulder, Paul A.;Hennekam, Raoul C.
SMC1A 编码粘连蛋白复合物的一种蛋白质。已知 SMC1A W 变体会导致类似于 Cornelia de Lange 综合征 (CdLS) 的表型。外显子组测序可以识别癫痫性脑病患者中与 CdLS 不相似的 SMC1A 变异。我们对 51 名具有 SMC1A 变异的个体的身体和行为特征进行了一项国际跨学科研究，并将结果与 67 名具有 NIPBL 变异的个体进行了比较。在荷兰，研究人员对所有已知的具有 SMC1A 变异的个体进行了研究，无论是否具有 CdLS 表型。具有SMC1A变异的个体可能类似于CdLS，但与具有NIPBL变异的个体相比，表现不太明显：生长受到较少干扰，面部体征不太明显（眼周体征和薄上朱红除外），没有重大的肢体异常，并且具有更高水平的认知和适应功能。 NIPBL 组的自残行为更频繁、更严重。在荷兰小组中，13 名个体中有 5 名（均为女性）的表型与雷特综合征非常相似：癫痫性脑病、严重或极重度智力障碍、刻板运动和（在某些情况下）退化。它们的错义、无义和移码突变均匀地分布在基因上。我们得出结论，SMC1A 变异可导致类似于 CdLS 的表型和类似于 Rett 综合征的表型。 SMC1A 组和 NIPBL 组之间的相似性表明，粘连蛋白功能紊乱导致了表型，但这些组之间的差异也可能由其他潜在机制（例如粘连蛋白基因的兼职）来解释。
SMC1A encodes one of the proteins of the cohesin complex. SMC1A Wvariants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.