RRC ID 55007
Author Fan Y, Yin W, Hu B, Kline AD, Zhang VW, 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.
Title De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism.
Journal Am J Hum Genet
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.
Volume 103(3)
Pages 448-455
Published 2018-9-6
DOI 10.1016/j.ajhg.2018.07.019
PII S0002-9297(18)30246-5
PMID 30122539
PMC PMC6128244
MeSH 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
IF 9.924
Times Cited 3
Zebrafish Tol-056