Huisman Sylvia, Mulder Paul A, Redeker Egbert, Bader Ingrid, Bisgaard Anne-Marie, Brooks Alice, Cereda Anna, Cinca Constanza, Clark Dinah, Cormier-Daire Valerie, Deardorff Matthew A, Diderich Karin, Elting Mariet, van Essen Anthonie, FitzPatrick David, Gervasini Cristina, Gillessen-Kaesbach Gabriele, Girisha Katta M, Hilhorst-Hofstee Yvonne, Hopman Saskia, Horn Denise, Isrie Mala, Jansen Sandra, Jespersgaard Cathrine, Kaiser Frank J, Kaur Maninder, Kleefstra Tjitske, Krantz Ian D, Lakeman Phillis, Landlust Annemiek, Lessel Davor, Michot Caroline, Moss Jo, Noon Sarah E, Oliver Chris, Parenti Ilaria, Pie Juan, Ramos Feliciano J, Rieubland Claudine, Russo Silvia, Selicorni Angelo, Tümer Zeynep, Vorstenbosch Rieneke, Wenger Tara L, van Balkom Ingrid, Piening Sigrid, Wierzba Jolanta, Hennekam Raoul C
Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Prinsenstichting Institute, Purmerend, the Netherlands.
Am J Med Genet A. 2017 Aug;173(8):2108-2125. doi: 10.1002/ajmg.a.38279. Epub 2017 May 26.
SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants 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.
SMC1A编码黏连蛋白复合体的一种蛋白质。已知SMC1A变异会导致一种类似于科妮莉亚·德·朗格综合征（CdLS）的表型。外显子组测序已使人们能够在患有癫痫性脑病但不像CdLS的个体中识别出SMC1A变异。我们对51名携带SMC1A变异的个体进行了一项国际多学科研究，以了解其身体和行为特征，并将结果与67名携带NIPBL变异的个体进行比较。在荷兰，对所有已知的携带SMC1A变异的个体进行了研究，包括有和没有CdLS表型的个体。携带SMC1A变异的个体可能类似于CdLS，但与携带NIPBL变异的个体相比，其表现不那么明显：生长发育受干扰程度较小，面部体征不那么明显（除了眼周体征和上唇朱红色变薄），没有严重的肢体异常，并且他们的认知和适应功能水平较高。自我伤害行为在NIPBL组中更频繁且更严重。在荷兰组的13名个体中有5名（均为女性）具有与雷特综合征显著相似的表型：癫痫性脑病、重度或极重度智力残疾、刻板动作以及（部分个体）发育倒退。他们的错义、无义和平移突变在基因中均匀分布。我们得出结论，SMC1A变异可导致类似于CdLS的表型和类似于雷特综合征的表型。SMC1A组和NIPBL组之间的相似性表明黏连蛋白功能紊乱导致了这种表型，但这些组之间的差异也可能由其他潜在机制解释，如黏连蛋白基因的兼职功能。
