title: Targeted Genes Sequencing Identified a Novel 15 bp Deletion on GJA8 in a Chinese Family with Autosomal Dominant Congenital Cataracts.
abstract: BACKGROUND
  Congenital cataract (CC) is the leading cause of visual impairment or blindness in children worldwide. Because of highly genetic and clinical heterogeneity, a molecular diagnosis of the lens disease remains a challenge.
  
  
  METHODS
  In this study, we tested a three-generation Chinese family with autosomal dominant CCs by targeted sequencing of 45 CC genes on next generation sequencing and evaluated the pathogenicity of the detected mutation by protein structure, pedigree validation, and molecular dynamics (MD) simulation.
  
  
  RESULTS
  A novel 15 bp deletion on GJA8 (c.426_440delGCTGGAGGGGACCCT or p. 143_147delLEGTL) was detected in the family. The deletion, concerned with an in-frame deletion of 5 amino acid residues in a highly evolutionarily conserved region within the cytoplasmic loop domain of the gap junction channel protein connexin 50 (Cx50), was in full cosegregation with the cataract phenotypes in the family but not found in 1100 control exomes. MD simulation revealed that the introduction of the deletion destabilized the Cx50 gap junction channel, indicating the deletion as a dominant-negative mutation.
  
  
  CONCLUSIONS
  The above results support the pathogenic role of the 15 bp deletion on GJA8 in the Chinese family and demonstrate targeted genes sequencing as a resolution to molecular diagnosis of CCs.
authors.affiliation: Department of Ophthalmology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Han-Yi
authors.initials: HY
authors.lastname: Min
authors.forename: Peng-Peng
authors.initials: PP
authors.lastname: Qiao
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Yan
authors.forename: Hui-Feng
authors.initials: HF
authors.lastname: Jiang
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Zhu
authors.forename: Hui-Qian
authors.initials: HQ
authors.lastname: Du
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002386:Cataract / Q000235:genetics*; D017630:Connexins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D009154:Mutation; D000099264:Connexin 50
chemical_list: D017630:Connexins; D000099264:Connexin 50