title: Targeted sequencing of 179 genes associated with hereditary retinal dystrophies and 10 candidate genes identifies novel and known mutations in patients with various retinal diseases.
abstract: OBJECTIVE
  Hereditary retinal dystrophies (HRDs) are a group of monogenic diseases characterized by an irreversible loss of photoreceptors. HRDs exhibit significant genetic and clinical heterogeneities challenging traditional techniques for determining disease-causal mutations. This study aims to develop an efficient molecular diagnostic platform for HRDs, and to determine the genetic basis for 25 randomly collected Chinese families with a variety of HRDs.
  
  
  METHODS
  We designed a high throughput sequence capture microarray targeting 179 genes associated with HRDs and 10 candidate genes. We combined sequence capture with next-generation sequencing (NGS) to screen for mutations in the cohort of Chinese families. Variants detected by NGS were filtered, validated, and prioritized by pathogenicity analysis. Genotypes and phenotypes were correlated.
  
  
  RESULTS
  We identified four recurrent single mutations, two compound mutations, and eight novel putative causative mutations, including five putative pathogenic alleles (e.g., premature stop codons and frame shifts) and three novel missense variants that are very likely pathogenic. These findings provided specific genetic diagnoses in 14 of 25 families (56%). Among these, identification of a mutation in VCAN in a family with a complicated phenotype helped to finalize the clinical diagnosis as Wagner syndrome. In another five families, 11 potential novel pathogenic variants were identified.
  
  
  CONCLUSIONS
  A substantial number of potential new genes and new mutations associated with HRDs remain to be discovered. Identification of the novel HRDs-causing mutations in our study not only provides a better understanding of genotype-phenotype relationships in these diseases, but also demonstrates that the approach described herein is an effective method for large scale mutation detection among diverse and complicated HRDs cases.
authors: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing, China.
authors: Xuejuan
authors: X
authors: Chen
authors: Kanxing
authors: K
authors: Zhao
authors: Xunlun
authors: X
authors: Sheng
authors: Yang
authors: Y
authors: Li
authors: Xiang
authors: X
authors: Gao
authors: Xiumei
authors: X
authors: Zhang
authors: Xiaoli
authors: X
authors: Kang
authors: Xinyuan
authors: X
authors: Pan
authors: Yuan
authors: Y
authors: Liu
authors: Chao
authors: C
authors: Jiang
authors: Houxia
authors: H
authors: Shi
authors: Xue
authors: X
authors: Chen
authors: Weining
authors: W
authors: Rong
authors: Li Jia
authors: LJ
authors: Chen
authors: Tim Yuk Yau
authors: TY
authors: Lai
authors: Yani
authors: Y
authors: Liu
authors: Xiuying
authors: X
authors: Wang
authors: Songtao
authors: S
authors: Yuan
authors: Qinghuai
authors: Q
authors: Liu
authors: Douglas
authors: D
authors: Vollrath
authors: Chi Pui
authors: CP
authors: Pang
authors: Chen
authors: C
authors: Zhao
mesh_terms: D044466:Asian People / Q000235:genetics; D002681:China; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D058499:Retinal Dystrophies / Q000151:congenital / Q000235:genetics*