背景:细胞周期蛋白依赖性激酶8(CDK8)是调节介体复合物活性的调节激酶模块的一部分。调解员,一个大的构象灵活的蛋白质复合物,继续调节RNA聚合酶II的活性,从而影响转录调控。因此,激酶模块内基因的失活突变导致异常的转录调控和疾病,即,CDK8相关智力发育障碍伴张力减退和行为异常(IDDHBA)。
方法:我们描述,第一次,一个可能的致病性杂合CDK8变异c.599G>A,p.(Arg200Gln)遗传自亲生母亲。儿童和母亲的临床表现在IDDHBA的所述临床范围内;然而,在儿童中还观察到了无证的髋部和膝盖进行性挛缩以及脊柱侧弯。在母亲中没有发现这种表型,突出显示同一家族中同一变体的异质表示。此外,所描述的临床表现可能进一步支持具有不同临床表现的模式或介体相关综合征的概念.
结论:本病例报告记录了首例IDDHBA的遗传病例,并扩大了CDK8相关疾病的表型范围,包括未记录的髋部和膝盖进行性挛缩以及脊柱侧凸,这可能支持具有不同临床表现的模态或介体相关综合征的概念。
Cyclin-dependent kinase 8 (CDK8) is part of a regulatory kinase module that regulates the activity of the Mediator complex. The Mediator, a large conformationally flexible protein complex, goes on to regulate RNA polymerase II activity, consequently affecting transcriptional regulation. Thus, inactivating mutations of the genes within the kinase module cause aberrant transcriptional regulation and disease, namely, CDK8-related intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA).
We describe, for the first time, a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother. The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA; however, undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child. This phenotype was not found in the mother, highlighting a heterogenous presentation for the same variant within the same family. Furthermore, the described clinical presentation may further support the notion of a module- or Mediator-related syndrome with varying clinical presentation.
This
case report documents the first inherited
case of IDDHBA and expands the phenotypic spectrum for CDK8-related disease to include undocumented progressive contractures of the hips and knees as well as scoliosis, which may support the notion of a module- or Mediator-related syndrome with varying clinical presentation.