title: Whole-exome sequencing reveals a novel CHM gene mutation in a family with choroideremia initially diagnosed as retinitis pigmentosa.
abstract: BACKGROUND
  Genomic mutations in about 200 genes are associated with hereditary retinal diseases. In this study, we screened for the disease-causing gene mutation in a family with X-linked retinal degenerative disease.
  
  
  METHODS
  Pedigree data were collected and genomic DNA was isolated from peripheral blood of family members, who also underwent comprehensive ophthalmic examination including visual acuity, slit-lamp examination, fundus examination and visual field testing at Qilu Hospital of Shandong University. Whole-exome genomic sequencing was used to screen for gene mutations in the male proband. Sanger sequencing was used to confirm the mutation revealed in this family.
  
  
  RESULTS
  Two affected males underwent ophthalmic examination; retinitis pigmentosa (RP) was diagnosed on the basis of night blindness beginning at an early age, decreasing visual acuity, progressive loss of peripheral vision, attenuation of retinal vessels and pigment disturbance on fundus examination. However, whole-exome sequencing revealed no mutation in RP-associated genes. Instead, we identified a novel hemizygous c.1475_1476insCA mutation in the choroideremia-associated gene (CHM). The mutation was confirmed by Sanger sequencing and further excluded from the possibility as a rare polymorphism. From the genetic data and clinical findings, the diagnosis was corrected to choroideremia (CHM). Further molecular genetic analysis suggested that this novel CHM mutation caused a frame shift (p.Leu492PhefsX7) and encoded a truncated nonfunctional Rab escort protein 1 (REP-1), which caused CHM in this family. Finally, sequencing data for a pregnant female member confirmed that she did not carry the mutation and thus was carrying a healthy infant.
  
  
  CONCLUSIONS
  We report a novel CHM mutation, c.1475_1476insCA, identified by whole-exome sequencing in a family with X-linked CHM initially diagnosed as RP. Our findings emphasize the value of a diagnostic approach that associates genetic and ophthalmologic data to facilitate the proper clinical diagnosis of rare hereditary retinal diseases such as CHM.
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, 107#, Wenhua Xi Road, Jinan, 250012, China. guohui516@126.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Medical Oncology, Cancer Center, Qilu Hospital of Shandong University, Jinan, China. lijisheng@gmail.com.
authors.forename: Jisheng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Genetics, Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, 250012, China. 793889916@qq.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Medical Genetics, Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, 250012, China. 89668289@qq.com.
authors.forename: Jiangxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, 107#, Wenhua Xi Road, Jinan, 250012, China. 43660756@qq.com.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Medical Genetics, Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, 250012, China. liuqiji@sdu.edu.cn.
authors.forename: Qiji
authors.initials: Q
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics; D015794:Choroideremia / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D059472:Exome / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012174:Retinitis Pigmentosa / Q000175:diagnosis*; D017422:Sequence Analysis, DNA; D014792:Visual Acuity; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D020691:rab GTP-Binding Proteins