title: Rapid and cost-effective molecular diagnosis using exome sequencing of one proband with autosomal dominant congenital cataract.
abstract: OBJECTIVE
  Due to high genetic heterogeneity, to exclude known mutations and map novel mutations in autosomal dominant congenital cataract (ADCC) using conventional candidate gene screening requires laborious laboratory work. We attempted to use a cost-effective exome sequencing strategy to identify disease-causing mutations in an ADCC pedigree.
  
  
  METHODS
  An ADCC pedigree affected by nuclear cataract and 200 unrelated senile cataract controls were recruited and given comprehensive ophthalmic examination. Whole exome of the proband of the family was captured by the Illumina TruSeq Exome Enrichment Kit, followed by sequencing using Illumina HiSeq 2000 sequencer. Validation was performed by direct sequencing.
  
  
  RESULTS
  The whole exome, including all exons of known ADCC disease-causing genes, was screened for possible disease-causing mutations. A recurrent missense mutation c.773C>T (p.S258F) in exon 2 of the gap junction protein alpha 8 gene (GJA8) was identified in the proband with nuclear cataract. The result was confirmed by direct sequencing. The mutation showed complete co-segregation with the disease phenotype in the family but was not observed in unrelated unaffected controls.
  
  
  CONCLUSIONS
  By successfully sequencing whole exome of only one proband and identifying a GJA8 mutation in one ADCC pedigree, the current study demonstrated that exome sequencing could serve as a rapid, robust, and cost-effective approach in clinical diagnosis and disease-causing gene discovery for ADCC.
authors.affiliation: 1] Joint Shantou International Eye Center, Shantou University and the Chinese University of Hong Kong, Shantou, China [2] Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: J-H
authors.identifier: 0000000187142543
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Joint Shantou International Eye Center, Shantou University and the Chinese University of Hong Kong, Shantou, China.
authors.forename: J
authors.initials: J
authors.lastname: Qiu
authors.affiliation: 1] Joint Shantou International Eye Center, Shantou University and the Chinese University of Hong Kong, Shantou, China [2] Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: 1] Joint Shantou International Eye Center, Shantou University and the Chinese University of Hong Kong, Shantou, China [2] Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: C P
authors.initials: CP
authors.lastname: Pang
authors.affiliation: Joint Shantou International Eye Center, Shantou University and the Chinese University of Hong Kong, Shantou, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
mesh_terms: D002386:Cataract / Q000175:diagnosis / Q000191:economics / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques / Q000191:economics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D000099264:Connexin 50
chemical_list: D017630:Connexins; D005136:Eye Proteins; D000099264:Connexin 50