Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
MVZ für Medizinische Genetik und Molekulare Medizin, Cologne, Germany.
Clin Genet. 2018 Nov;94(5):450-456. doi: 10.1111/cge.13412. Epub 2018 Aug 9.
MED12 is a member of the large Mediator complex that controls cell growth, development, and differentiation. Mutations in MED12 disrupt neuronal gene expression and lead to at least three distinct X-linked intellectual disability syndromes (FG, Lujan-Fryns, and Ohdo). Here, we describe six families with missense variants in MED12 (p.(Arg815Gln), p.(Val954Gly), p.(Glu1091Lys), p.(Arg1295Cys), p.(Pro1371Ser), and p.(Arg1148His), the latter being first reported in affected females) associated with a continuum of symptoms rather than distinct syndromes. The variants expanded the genetic architecture and phenotypic spectrum of MED12-related disorders. New clinical symptoms included brachycephaly, anteverted nares, bulbous nasal tip, prognathism, deep set eyes, and single palmar crease. We showed that MED12 variants, initially implicated in X-linked recessive disorders in males, may predict a potential risk for phenotypic expression in females, with no correlation of the X chromosome inactivation pattern in blood cells. Molecular modeling (Yasara Structure) performed to model the functional effects of the variants strongly supported the pathogenic character of the variants examined. We showed that molecular modeling is a useful method for in silico testing of the potential functional effects of MED12 variants and thus can be a valuable addition to the interpretation of the clinical and genetic findings.
MED12 是 Mediator 复合物的一个成员，该复合物控制细胞生长、发育和分化。MED12 中的突变会破坏神经元基因表达，导致至少三种不同的 X 连锁智力障碍综合征（FG、Lujan-Fryns 和 Ohdo）。在这里，我们描述了六个家族，这些家族中的 MED12 存在错义变异（p.(Arg815Gln)、p.(Val954Gly)、p.(Glu1091Lys)、p.(Arg1295Cys)、p.(Pro1371Ser)和 p.(Arg1148His)，后一种变异首次在受影响的女性中报道），这些变异与一系列症状相关，而不是特定的综合征。这些变异扩大了 MED12 相关疾病的遗传结构和表型谱。新的临床症状包括短头畸形、前鼻孔外翻、球状鼻尖、下颌前突、深陷的眼睛和单一掌褶。我们表明，最初被认为与男性 X 连锁隐性疾病相关的 MED12 变异可能预示着女性表型表达的潜在风险，而血细胞中 X 染色体失活模式没有相关性。进行的分子建模（Yasara Structure）模拟了变异的功能效应，强烈支持了所研究变异的致病性特征。我们表明，分子建模是一种用于 MED12 变异潜在功能效应的计算机模拟测试的有用方法，因此可以作为解释临床和遗传发现的有用补充。
