2. Academic Validation
  3. De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy

De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy

  • Am J Hum Genet. 2020 May 7;106(5):717-725. doi: 10.1016/j.ajhg.2020.04.001.
Hyung-Lok Chung 1,  Xiao Mao 2,  Hua Wang 2,  Ye-Jin Park 3,  Paul C Marcogliese 4,  Jill A Rosenfeld 3,  Lindsay C Burrage 3,  Pengfei Liu 5,  David R Murdock 3,  Shinya Yamamoto 4,  Michael F Wangler 4,  Undiagnosed Diseases Network,  Hsiao-Tuan Chao 6,  Hongyu Long 7,  Li Feng 7,  Carlos A Bacino 3,  Hugo J Bellen 8,  Bo Xiao 9
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 National Health Commission Key Laboratory of Birth Defects Research, Prevention, and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, China; Department of Medical Genetics, Maternal and Child Health Hospital of Hunan Province, Changsha, Hunan 410008, China.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 22021, USA.
  • 6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, TX 77030, USA.
  • 7 Neurology Department, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 8 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
  • 9 Neurology Department, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: [email protected].
PMID: 32330417 DOI: 10.1016/j.ajhg.2020.04.001
Abstract

We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of CDK8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of CDK8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of CDK8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of CDK8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of CDK8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.

Keywords

Cdk8; Drosophila; West syndrome; bang sensitivity; de novo; dominant variants; genetic disease; infantile spasms; rare disease; seizure.

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