SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females
SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females
复制标题
DOI：
10.1016/j.ajhg.2021.01.015
复制
发表时间：
2021-03-04
影响因子：
9.8
通讯作者：
Tartaglia, Marco
中科院分区：
文献类型：
--
作者：
Radio, Francesca Clementina;Pang, Kaifang;Tartaglia, Marco
缺失1 p36（del 1 p36）综合征是由末端常染色体缺失引起的最常见的人类疾病。这种情况是分子和临床异质性。涉及两个非重叠区域的缺失，称为远端（端粒）和近端（着丝粒）关键区域，足以引起大多数复发性临床特征，尽管具有不同的面部特征和畸形。SPEN编码一种转录抑制因子，通常在近端del 1 p36综合征中缺失，位于近端1 p36关键区的着丝粒。在这里，我们使用了来自34个SPEN截断变异个体的临床数据来定义一种神经发育障碍，其特征与近端del 1 p36综合征的特征有很大重叠。这种疾病的临床特征包括发育迟缓/智力残疾、自闭症谱系障碍、焦虑、攻击行为、注意力缺陷障碍、张力减退、脑和脊柱异常、先天性心脏缺陷、高/窄腭、面部畸形和肥胖/BMI增加，尤其是女性。通过共表达分析，SPEN也成为del 1 p36综合征的相关基因。最后，我们发现SPEN的单倍不足与受影响女性的X染色体的独特DNA甲基化episignature相关，进一步证明了该蛋白质对该染色体的表观遗传控制的特定贡献，以及X染色体特异性episignature分类综合征特征的范例。我们的结论是，SPEN是需要多个发展过程和SPEN单倍不足是一个主要的贡献者与先前建立的1 p36关键区域的着丝粒缺失相关的疾病。
Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.