TY - JOUR
T1 - De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism
AU - Fan, Yanjie
AU - Yin, Wu
AU - Hu, Bing
AU - Kline, Antonie D.
AU - Zhang, Victor Wei
AU - Liang, Desheng
AU - Sun, Yu
AU - Wang, Lili
AU - Tang, Sha
AU - Powis, Zöe
AU - Li, Lei
AU - Yan, Huifang
AU - Shi, Zhen
AU - Yang, Xiaoping
AU - Chen, Yinyin
AU - Wang, Jingmin
AU - Jiang, Yuwu
AU - Tan, Hu
AU - Gu, Xuefan
AU - Wu, Lingqian
AU - Yu, Yongguo
N1 - Funding Information:
The authors thank Dr. Feng Zhang for constructive comments, Dr. S. Higashijima for the tol-056 transgenic fish line, Jiu-Lin Du for the zebrafish AB strain, Tin-Xi Liu for providing the gift of pCS2+ vector, and Xia Zhang, Zhiqing Hu, Yue Tao, Nan Shen, and Xi Mo for assisting the experiments during the revision. This work was supported by the National Natural Science Foundation of China (no. 81500972 to Y.F., no. 81670812 to Y.Y., no. 31571313 to D.L., no. 31571068 to B.H.), the Shanghai Municipal Education Commission (no. 15CG14 to Y.F.), the Jiaotong University Cross Biomedical Engineering (no. YG2017MS72 to Y.Y.), the Shanghai Municipal Commission of Health and Family Planning (no. 201740192 to Y.Y.), the Shanghai Shen Kang Hospital Development Center new frontier technology joint project (no. SHDC12017109 to Y.Y.), China Postdoctoral Science Foundation (no. 2015M571941 to W.Y.), the Fundamental Research Funds for the Central Universities (to W.Y.), and the National Key R&D Program of China (no. SQ2017YFSF080012 to L. Wu).
Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/9/6
Y1 - 2018/9/6
N2 - 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.
AB - 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.
KW - CCNK
KW - de novo mutations
KW - developmental delay/intellectual disability
KW - facial dysmorphism
KW - zebrafish model
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U2 - 10.1016/j.ajhg.2018.07.019
DO - 10.1016/j.ajhg.2018.07.019
M3 - Article
C2 - 30122539
AN - SCOPUS:85056417901
SN - 0002-9297
VL - 103
SP - 448
EP - 455
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -