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Am J Hum Genet. 2018 Sep 6;103(3):448-455. doi: 10.1016/j.ajhg.2018.07.019. Epub 2018 Aug 16.

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

Author information

1
Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
2
Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
3
Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; AmCare Genomics Lab, GuangZhou 510300, China.
5
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410008, China.
6
Ambry Genetics, Aliso Viejo, CA 92656, USA.
7
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
8
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China; Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province 030001, China.
9
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410008, China. Electronic address: wulingqian@sklmg.edu.cn.
10
Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China. Electronic address: yuyongguo@shsmu.edu.cn.

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.

KEYWORDS:

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

PMID:
30122539
PMCID:
PMC6128244
DOI:
10.1016/j.ajhg.2018.07.019
[Indexed for MEDLINE]
Free PMC Article

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