Human Genetics

, Volume 133, Issue 3, pp 331–345 | Cite as

Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements

  • Feng Wang
  • Hui Wang
  • Han-Fang Tuan
  • Duy H. Nguyen
  • Vincent Sun
  • Vafa Keser
  • Sara J. Bowne
  • Lori S. Sullivan
  • Hongrong Luo
  • Ling Zhao
  • Xia Wang
  • Jacques E. Zaneveld
  • Jason S. Salvo
  • Sorath Siddiqui
  • Louise Mao
  • Dianna K. Wheaton
  • David G. Birch
  • Kari E. Branham
  • John R. Heckenlively
  • Cindy Wen
  • Ken Flagg
  • Henry Ferreyra
  • Jacqueline Pei
  • Ayesha Khan
  • Huanan Ren
  • Keqing Wang
  • Irma Lopez
  • Raheel Qamar
  • Juan C. Zenteno
  • Raul Ayala-Ramirez
  • Beatriz Buentello-Volante
  • Qing Fu
  • David A. Simpson
  • Yumei Li
  • Ruifang Sui
  • Giuliana Silvestri
  • Stephen P. Daiger
  • Robert K. Koenekoop
  • Kang Zhang
  • Rui Chen
Original Investigation

Abstract

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.

Supplementary material

439_2013_1381_MOESM1_ESM.docx (39 kb)
Supplementary material 1 (DOCX 39 kb)
439_2013_1381_MOESM2_ESM.pptx (5.3 mb)
Supplementary material 2 (PPTX 5463 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Feng Wang
    • 1
    • 2
  • Hui Wang
    • 1
    • 2
  • Han-Fang Tuan
    • 1
  • Duy H. Nguyen
    • 3
  • Vincent Sun
    • 4
  • Vafa Keser
    • 4
  • Sara J. Bowne
    • 5
  • Lori S. Sullivan
    • 5
  • Hongrong Luo
    • 3
    • 6
  • Ling Zhao
    • 3
    • 6
  • Xia Wang
    • 1
    • 2
  • Jacques E. Zaneveld
    • 1
    • 2
  • Jason S. Salvo
    • 1
    • 7
  • Sorath Siddiqui
    • 4
  • Louise Mao
    • 3
  • Dianna K. Wheaton
    • 8
  • David G. Birch
    • 8
  • Kari E. Branham
    • 9
  • John R. Heckenlively
    • 9
  • Cindy Wen
    • 3
  • Ken Flagg
    • 3
  • Henry Ferreyra
    • 3
  • Jacqueline Pei
    • 3
  • Ayesha Khan
    • 4
  • Huanan Ren
    • 4
  • Keqing Wang
    • 1
  • Irma Lopez
    • 4
  • Raheel Qamar
    • 10
    • 11
  • Juan C. Zenteno
    • 12
  • Raul Ayala-Ramirez
    • 12
  • Beatriz Buentello-Volante
    • 12
  • Qing Fu
    • 13
  • David A. Simpson
    • 14
  • Yumei Li
    • 1
    • 2
  • Ruifang Sui
    • 15
  • Giuliana Silvestri
    • 14
  • Stephen P. Daiger
    • 5
    • 16
  • Robert K. Koenekoop
    • 4
  • Kang Zhang
    • 3
    • 6
    • 17
  • Rui Chen
    • 1
    • 2
    • 7
    • 18
    • 19
  1. 1.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  2. 2.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  3. 3.Institute for Genomic Medicine and Shiley Eye CenterUniversity of California San DiegoLa JollaUSA
  4. 4.McGill Ocular Genetics Laboratory, Division of Paediatric Ophthalmology, Departments of Human Genetics, Paediatric Surgery and OphthalmologyMcGill University Health CentreMontrealCanada
  5. 5.Human Genetics Center, School of Public HealthThe University of Texas Health Science CenterHoustonUSA
  6. 6.Molecular Medicine Research Center and Department of Ophthalmology, West China HospitalSichuan UniversityChengduChina
  7. 7.Structural and Computational Biology and Molecular Biophysics Graduate ProgramHoustonUSA
  8. 8.The Retina Foundation of the SouthwestDallasUSA
  9. 9.Department of Ophthalmology and Visual Sciences, Kellogg Eye CenterUniversity of MichiganAnn ArborUSA
  10. 10.COMSATS Institute of Information TechnologyIslamabadPakistan
  11. 11.Al-Nafees Medical College and HospitalIsra UniversityIslamabadPakistan
  12. 12.Department of Genetics-Research Unit, Institute of Ophthalmology “Conde de Valenciana” and Biochemistry Department, Faculty of MedicineUNAMMexico CityMexico
  13. 13.Department of Ophthalmology, North Huashan HospitalFudan UniversityShanghaiChina
  14. 14.Centre for Vision and Vascular Science, Clinical ICS-AQueen’s University BelfastBelfastUK
  15. 15.Department of Ophthalmology, Peking Union Medical College HospitalPeking Union Medical CollegeBeijingChina
  16. 16.Department of Ophthalmology and Visual ScienceThe University of Texas Health Science CenterHoustonUSA
  17. 17.Veterans Administration Healthcare SystemSan DiegoUSA
  18. 18.The Verna and Marrs McLean Department of Biochemistry and Molecular BiologyBaylor College of MedicineHoustonUSA
  19. 19.Program in Developmental BiologyBaylor College of MedicineHoustonUSA

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