De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism

Yanjie Fan, Wu Yin, Bing Hu, Antonie D. Kline, Victor Wei Zhang, Desheng Liang, Yu Sun, Lili Wang, Sha Tang, Zöe Powis, Lei Li, Huifang Yan, Zhen Shi, Xiaoping Yang, Yinyin Chen, Jingmin Wang, Yuwu Jiang, Hu Tan, Xuefan Gu, Lingqian WuYongguo Yu

Research output: Contribution to journalArticlepeer-review


Neurodevelopment is a transcriptionally orchestrated process. Cyclin K, a regulator of transcription encoded by CCNK, is thought to play a critical role in the RNA polymerase II-mediated activities. However, dysfunction of CCNK has not been linked to genetic disorders. In this study, we identified three unrelated individuals harboring de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region and one individual harboring a de novo nonsynonymous variant c.331A>G (p.Lys111Glu) in CCNK. These four individuals, though from different ethnic backgrounds, shared a common phenotype of developmental delay and intellectual disability (DD/ID), language defects, and distinctive facial dysmorphism including high hairline, hypertelorism, thin eyebrows, dysmorphic ears, broad nasal bridge and tip, and narrow jaw. Functional assay in zebrafish larvae showed that Ccnk knockdown resulted in defective brain development, small eyes, and curly spinal cord. These defects were partially rescued by wild-type mRNA coding CCNK but not the mRNA with the identified likely pathogenic variant c.331A>G, supporting a causal role of CCNK variants in neurodevelopmental disorders. Taken together, we reported a syndromic neurodevelopmental disorder with DD/ID and facial characteristics caused by CCNK variations, possibly through a mechanism of haploinsufficiency.

Original languageEnglish (US)
Pages (from-to)448-455
Number of pages8
JournalAmerican journal of human genetics
Issue number3
StatePublished - Sep 6 2018


  • CCNK
  • de novo mutations
  • developmental delay/intellectual disability
  • facial dysmorphism
  • zebrafish model

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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