PUBLICATION
De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism
- Authors
- Fan, Y., Yin, W., Hu, B., Kline, A.D., Zhang, V.W., Liang, D., Sun, Y., Wang, L., Tang, S., Powis, Z., Li, L., Yan, H., Shi, Z., Yang, X., Chen, Y., Wang, J., Jiang, Y., Tan, H., Gu, X., Wu, L., Yu, Y.
- ID
- ZDB-PUB-180821-2
- Date
- 2018
- Source
- American journal of human genetics 103(3): 448-455 (Journal)
- Registered Authors
- Keywords
- CCNK, de novo mutations, developmental delay/intellectual disability, facial dysmorphism, zebrafish model
- MeSH Terms
-
- Abnormalities, Multiple/genetics*
- Adolescent
- Animals
- Child
- Child, Preschool
- Craniofacial Abnormalities/genetics*
- Cyclins/genetics*
- Developmental Disabilities/genetics*
- Female
- Haploinsufficiency/genetics
- Heterozygote
- Humans
- Hypertelorism/genetics
- Intellectual Disability/genetics
- Male
- Muscular Atrophy/genetics*
- Musculoskeletal Abnormalities/genetics
- Mutation/genetics*
- Nervous System Malformations/genetics
- Neurodevelopmental Disorders/genetics*
- Phenotype
- Syndrome
- Zebrafish
- PubMed
- 30122539 Full text @ Am. J. Hum. Genet.
Citation
Fan, Y., Yin, W., Hu, B., Kline, A.D., Zhang, V.W., Liang, D., Sun, Y., Wang, L., Tang, S., Powis, Z., Li, L., Yan, H., Shi, Z., Yang, X., Chen, Y., Wang, J., Jiang, Y., Tan, H., Gu, X., Wu, L., Yu, Y. (2018) De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism. American journal of human genetics. 103(3):448-455.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping