Expanding the phenotypic spectrum for CDK8‐related disease: A case report

• Published in: American journal of medical genetics. Part A 2024-05, Vol.194 (5), p.e63537-n/a
• Main Authors: Comeau, Dominique, Belliveau, Jenna, Bouhamdani, Nadia, Amor, Mouna Ben
• Format: Article
• Language: English
• Subjects: Case reports; CDK8; Child; Contracture - diagnosis; Contracture - genetics; Cyclin-Dependent Kinase 8 - genetics; DNA-directed RNA polymerase; Gene regulation; Hip; Humans; intellectual developmental disorder with hypotonia and behavioral abnormalities; Kinases; Knee; mediator complex; Mediator Complex - genetics; Mutation; Phenotypes; RNA polymerase; Scoliosis
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.63537

Background 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). Case Presentation 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. Conclusion 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.