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Original article
Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing
  1. Xia Wang1,2,
  2. Hui Wang1,2,
  3. Vincent Sun3,
  4. Han-Fang Tuan1,
  5. Vafa Keser3,
  6. Keqing Wang2,
  7. Huanan Ren3,
  8. Irma Lopez3,
  9. Jacques E Zaneveld1,2,
  10. Sorath Siddiqui3,
  11. Stephanie Bowles1,
  12. Ayesha Khan3,
  13. Jason Salvo1,4,
  14. Samuel G Jacobson5,
  15. Alessandro Iannaccone6,
  16. Feng Wang1,2,
  17. David Birch7,
  18. John R Heckenlively8,
  19. Gerald A Fishman9,
  20. Elias I Traboulsi10,
  21. Yumei Li1,2,
  22. Dianna Wheaton7,
  23. Robert K Koenekoop3,
  24. Rui Chen1,2,4,11
  1. 1Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA
  2. 2Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  3. 3McGill Ocular Genetics Laboratory (MOGL), Departments of Paediatric Surgery, Human Genetics and Ophthalmology, Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada
  4. 4Structural and Computational Biology & Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, USA
  5. 5Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  6. 6Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, USA
  7. 7Retina Foundation of the Southwest and Department of Ophthalmology, University of Texas Southwestern Medical School, Dallas, Texas, USA
  8. 8Department of Ophthalmology and Visual Sciences Center for Retinal and Macular Degeneration, University of Michigan, Ann Arbor, Michigan, USA
  9. 9The Chicago Lighthouse for the Blind and Visually Impaired, Chicago, Illinois, USA
  10. 10Ophthalmology, Cleveland Clinic, Cleveland, Ohio, USA
  11. 11Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA
  1. Correspondence to Dr Rui Chen, Human Genome Sequencing Center, One Baylor Plaza, Houston, Texas, US, 77054, Dr Robert K Koenekoop, McGill Ocular Genetics Laboratory,Montreal Children's Hospital, McGill University Health Centre, 2300 Tupper, Montreal, Quebec H3H 1P3 Canada,


Background Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments.

Methods We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis.

Results Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients.

Conclusions We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis.

  • Genetic screening/counselling
  • Clinical genetics
  • Ophthalmology
  • Vision research
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