title: Identification of a Novel Mutation in BRD4 that Causes Autosomal Dominant Syndromic Congenital Cataracts Associated with Other Neuro-Skeletal Anomalies.
abstract: Congenital cataracts can occur as a non-syndromic isolated ocular disease or as a part of genetic syndromes accompanied by a multi-systemic disease. Approximately 50% of all congenital cataract cases have a heterogeneous genetic basis. Here, we describe three generations of a family with an autosomal dominant inheritance pattern and common complex phenotypes, including bilateral congenital cataracts, short stature, macrocephaly, and minor skeletal anomalies. We did not find any chromosomal aberrations or gene copy number abnormalities using conventional genetic tests; accordingly, we conducted whole-exome sequencing (WES) to identify disease-causing genetic alterations in this family. Based on family WES data, we identified a novel BRD4 missense mutation as a candidate causal variant and performed cell-based experiments by ablation of endogenous BRD4 expression in human lens epithelial cells. The protein expression levels of connexin 43, p62, LC3BII, and p53 differed significantly between control cells and cells in which endogenous BRD4 expression was inhibited. We inferred that a BRD4 missense mutation was the likely disease-causing mutation in this family. Our findings may improve the molecular diagnosis of congenital cataracts and support the use of WES to clarify the genetic basis of complex diseases.
authors.affiliation: Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam, Republic of Korea.
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Jin
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Jeonhyun
authors.initials: J
authors.lastname: Kim
authors.affiliation: C&K Genomics, Seoul, Republic of Korea.
authors.forename: Woori
authors.initials: W
authors.lastname: Kwak
authors.affiliation: Department of Animal Sciences, University of Illinois, Urbana, Illinois, United States of America.
authors.forename: Hyeonsoo
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Gyu-Bin
authors.initials: GB
authors.lastname: Lim
authors.affiliation: Department of Pediatrics, Nowon Eulji Medical Center, Eulji University, Seoul, Republic of Korea.
authors.forename: Cha Gon
authors.identifier: http://orcid.org/0000-0001-7294-229X
authors.initials: CG
authors.lastname: Lee
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D001848:Bone Diseases, Developmental / Q000150:complications / Q000235:genetics*; D002386:Cataract / Q000150:complications / Q000151:congenital / Q000235:genetics*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000150:complications / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins