Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation
Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation
复制标题
DOI：
10.1016/j.ejmg.2017.06.004
复制
发表时间：
2017-09-01
影响因子：
1.9
通讯作者：
Rauch, Anita
中科院分区：
文献类型：
--
作者：
Asadollahi, Reza;Zweier, Markus;Rauch, Anita
在2003年将MED 13 L指定为一种基因并将其与智力残疾（ID）和大动脉环状转位联系起来十年后，我们先前描述了一种可识别的综合征，该综合征是由于MED 13 L单倍不足引起的。随后的22例通过全基因组检测诊断的患者的报告进一步描述了该综合征的表型谱扩展，并显示先天性心脏病的发病率降低。我们现在报告两个新的患者确定的全外显子组测序，一个与从头MED 13 L截短突变，另一个与从头错义突变。第一名患者表明与Kleefstra综合征有一些面部相似性，作为一种新的鉴别诊断，第二名患者首次显示MED 13 L错义突变复发。（Asp860Gly））。值得注意的是，我们的计算机模拟预测这种错义突变会降低α-螺旋的稳定性，从而影响MED 13 L二级结构，而大多数已发表的错义突变仍然是意义不确定的变体。对报告的MED 13 L单倍不足患者的审查表明，所有患者均存在中度至重度ID和面部异常，大多数患者存在重度言语延迟和肌肉张力减退。其他常见体征包括髓鞘形成缺陷和异常胼胝体的异常MRI结果、共济失调和协调问题、自闭症特征、癫痫发作/异常EEG或先天性心脏缺陷，约20-50%的患者存在这些异常MRI结果。关于面部异常，据报告，大多数患者表现为宽/突出的前额、低位耳、双颞狭窄、上斜的睑裂、凹陷/扁平的鼻梁、球鼻和异常的下巴，但也观察到约30%的巨舌症和水平眉毛。后者在1 p36缺失和Kleefstra综合征的鉴别诊断中尤其重要，而更常见的面部完形显示出与22q11.2缺失综合征的一些相似之处。尽管MED 13 L被发现是解密发育障碍研究中最常见的ID基因之一，但需要进一步详细的患者描述来探索完整的临床谱，潜在的基因型-表型相关性，以及错义突变的作用和基因沿着潜在的突变热点。(C)2017作者由Elsevier Masson SAS出版。
A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextrolooped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20-50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in similar to 30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome.Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene. (C) 2017 The Authors. Published by Elsevier Masson SAS.