Advertisement

Human Genetics

, Volume 134, Issue 2, pp 217–230 | Cite as

Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland

  • Li Zhao
  • Feng Wang
  • Hui Wang
  • Yumei Li
  • Sharon Alexander
  • Keqing Wang
  • Colin E. Willoughby
  • Jacques E. Zaneveld
  • Lichun Jiang
  • Zachry T. Soens
  • Philip Earle
  • David Simpson
  • Giuliana SilvestriEmail author
  • Rui ChenEmail author
Original Investigation

Abstract

Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive photoreceptor degeneration. An accurate molecular diagnosis is essential for disease characterization and clinical prognoses. A retinal capture panel that enriches 186 known retinal disease genes, including 55 known RP genes, was developed. Targeted next-generation sequencing was performed for a cohort of 82 unrelated RP cases from Northern Ireland, including 46 simplex cases and 36 familial cases. Disease-causing mutations were identified in 49 probands, including 28 simplex cases and 21 familial cases, achieving a solving rate of 60 %. In total, 65 pathogenic mutations were found, and 29 of these were novel. Interestingly, the molecular information of 12 probands was neither consistent with their initial inheritance pattern nor clinical diagnosis. Further clinical reassessment resulted in a refinement of the clinical diagnosis in 11 patients. This is the first study to apply next-generation sequencing-based, comprehensive molecular diagnoses to a large number of RP probands from Northern Ireland. Our study shows that molecular information can aid clinical diagnosis, potentially changing treatment options, current family counseling and management.

Keywords

Retinitis Pigmentosa Retinal Disease Usher Syndrome CDH23 Mutation Retinitis Pigmentosa Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We gratefully acknowledge all participating patients and their family members. R.C. is supported by grants from Retinal Research Foundation, Foundation Fighting Blindness (BR-GE-0613-0618-BCM) and the National Eye Institute (R01EY022356, R01EY018571). F.W. is supported by predoctoral fellowship: The Burroughs Wellcome Fund, The Houston Laboratory and Population Sciences Training Program in Gene Environment Interaction.

Conflict of interest

The authors declare no conflict of interest.

Ethical standards

This research was conducted in accordance with the Tenets of the declaration of Helsinki. Ethical permission was granted through ORECNI and all patients gave written consent to participate in the study.

Supplementary material

439_2014_1512_MOESM1_ESM.pdf (574 kb)
Supplementary material 1 (PDF 573 kb)

References

  1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249. doi: 10.1038/nmeth0410-248 PubMedCentralPubMedCrossRefGoogle Scholar
  2. Aller E, Jaijo T, Beneyto M, Najera C, Oltra S, Ayuso C, Baiget M, Carballo M, Antinolo G, Valverde D, Moreno F, Vilela C, Collado D, Perez-Garrigues H, Navea A, Millan JM (2006) Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet 43(11):e55. doi: 10.1136/jmg.2006.041764 PubMedCentralPubMedCrossRefGoogle Scholar
  3. Aller E, Larrieu L, Jaijo T, Baux D, Espinos C, Gonzalez-Candelas F, Najera C, Palau F, Claustres M, Roux AF, Millan JM (2010) The USH2A c.2299delG mutation: dating its common origin in a Southern European population. Eur J Hum Genet 18(7):788–793. doi: 10.1038/ejhg.2010.14 PubMedCentralPubMedCrossRefGoogle Scholar
  4. Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR (1997) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 15(3):236–246. doi: 10.1038/ng0397-236 PubMedCrossRefGoogle Scholar
  5. Anasagasti A, Barandika O, Irigoyen C, Benitez BA, Cooper B, Cruchaga C, Lopez de Munain A, Ruiz-Ederra J (2013) Genetic high throughput screening in Retinitis Pigmentosa based on high resolution melting (HRM) analysis. Exp Eye Res 116:386–394PubMedCrossRefGoogle Scholar
  6. Avila-Fernandez A, Cantalapiedra D, Aller E, Vallespin E, Aguirre-Lamban J, Blanco-Kelly F, Corton M, Riveiro-Alvarez R, Allikmets R, Trujillo-Tiebas MJ, Millan JM, Cremers FP, Ayuso C (2010) Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray. Mol Vis 16:2550–2558PubMedCentralPubMedGoogle Scholar
  7. Bader I, Brandau O, Achatz H, Apfelstedt-Sylla E, Hergersberg M, Lorenz B, Wissinger B, Wittwer B, Rudolph G, Meindl A, Meitinger T (2003) X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15. Invest Ophthalmol Vis Sci 44(4):1458–1463PubMedCrossRefGoogle Scholar
  8. Baldwin EJ, Gibberd FB, Harley C, Sidey MC, Feher MD, Wierzbicki AS (2010) The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease. J Neurol Neurosurg Psychiatry 81(9):954–957. doi: 10.1136/jnnp.2008.161059 PubMedCrossRefGoogle Scholar
  9. Bandah-Rozenfeld D, Mizrahi-Meissonnier L, Farhy C, Obolensky A, Chowers I, Pe’er J, Merin S, Ben-Yosef T, Ashery-Padan R, Banin E, Sharon D (2010) Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal-recessive retinitis pigmentosa. Am J Hum Genet 87(3):382–391. doi: 10.1016/j.ajhg.2010.07.022 PubMedCentralPubMedCrossRefGoogle Scholar
  10. Baux D, Larrieu L, Blanchet C, Hamel C, Ben Salah S, Vielle A, Gilbert-Dussardier B, Holder M, Calvas P, Philip N, Edery P, Bonneau D, Claustres M, Malcolm S, Roux AF (2007) Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients. Hum Mutat 28(8):781–789. doi: 10.1002/humu.20513 PubMedCrossRefGoogle Scholar
  11. Benaglio P, McGee TL, Capelli LP, Harper S, Berson EL, Rivolta C (2011) Next generation sequencing of pooled samples reveals new SNRNP200 mutations associated with retinitis pigmentosa. Hum Mutat 32(6):E2246–E2258. doi: 10.1002/humu.21485 PubMedCrossRefGoogle Scholar
  12. Bharadwaj AK, Kasztejna JP, Huq S, Berson EL, Dryja TP (2000) Evaluation of the myosin VIIA gene and visual function in patients with Usher syndrome type I. Exp Eye Res 71(2):173–181. doi: 10.1006/exer.2000.0863 PubMedCrossRefGoogle Scholar
  13. Bolz H, von Brederlow B, Ramirez A, Bryda EC, Kutsche K, Nothwang HG, Seeliger M, del CSCM, Vila MC, Molina OP, Gal A, Kubisch C (2001) Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet 27(1):108–112. doi: 10.1038/83667 PubMedCrossRefGoogle Scholar
  14. Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP (2001) Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci 42(10):2229–2236PubMedGoogle Scholar
  15. Challis D, Yu J, Evani US, Jackson AR, Paithankar S, Coarfa C, Milosavljevic A, Gibbs RA, Yu F (2012) An integrative variant analysis suite for whole exome next-generation sequencing data. BMC Bioinform 13:8. doi: 10.1186/1471-2105-13-8 CrossRefGoogle Scholar
  16. Chandler KE, Biswas S, Lloyd IC, Parry N, Clayton-Smith J, Black GC (2002) The ophthalmic findings in Cohen syndrome. Br J Ophthalmol 86(12):1395–1398PubMedCentralPubMedCrossRefGoogle Scholar
  17. Chang S, Vaccarella L, Olatunji S, Cebulla C, Christoforidis J (2011) Diagnostic challenges in retinitis pigmentosa: genotypic multiplicity and phenotypic variability. Curr Genomics 12(4):267–275. doi: 10.2174/138920211795860116 PubMedCentralPubMedCrossRefGoogle Scholar
  18. Chun S, Fay JC (2009) Identification of deleterious mutations within three human genomes. Genome Res 19(9):1553–1561. doi: 10.1101/gr.092619.109 PubMedCentralPubMedCrossRefGoogle Scholar
  19. Clark GR, Crowe P, Muszynska D, O’Prey D, O’Neill J, Alexander S, Willoughby CE, McKay GJ, Silvestri G, Simpson DA (2010) Development of a diagnostic genetic test for simplex and autosomal recessive retinitis pigmentosa. Ophthalmology 117(11):2169–2177 e2163. doi: 10.1016/j.ophtha.2010.02.029 PubMedCrossRefGoogle Scholar
  20. Coussa RG, Traboulsi EI (2012) Choroideremia: a review of general findings and pathogenesis. Ophthalmic Genet 33(2):57–65. doi: 10.3109/13816810.2011.620056 PubMedCrossRefGoogle Scholar
  21. Cremers FP, Kimberling WJ, Kulm M, de Brouwer AP, van Wijk E, te Brinke H, Cremers CW, Hoefsloot LH, Banfi S, Simonelli F, Fleischhauer JC, Berger W, Kelley PM, Haralambous E, Bitner-Glindzicz M, Webster AR, Saihan Z, De Baere E, Leroy BP, Silvestri G, McKay GJ, Koenekoop RK, Millan JM, Rosenberg T, Joensuu T, Sankila EM, Weil D, Weston MD, Wissinger B, Kremer H (2007) Development of a genotyping microarray for Usher syndrome. J Med Genet 44(2):153–160. doi: 10.1136/jmg.2006.044784 PubMedCentralPubMedCrossRefGoogle Scholar
  22. Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S (2010) Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol 6(12):e1001025. doi: 10.1371/journal.pcbi.1001025 PubMedCentralPubMedCrossRefGoogle Scholar
  23. den Hollander AI, ten Brink JB, de Kok YJ, van Soest S, van den Born LI, van Driel MA, van de Pol DJ, Payne AM, Bhattacharya SS, Kellner U, Hoyng CB, Westerveld A, Brunner HG, Bleeker-Wagemakers EM, Deutman AF, Heckenlively JR, Cremers FP, Bergen AA (1999) Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat Genet 23(2):217–221. doi: 10.1038/13848 CrossRefGoogle Scholar
  24. den Hollander AI, Black A, Bennett J, Cremers FP (2010) Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies. J Clin Invest 120(9):3042–3053. doi: 10.1172/JCI42258 CrossRefGoogle Scholar
  25. Dreyer B, Brox V, Tranebjaerg L, Rosenberg T, Sadeghi AM, Moller C, Nilssen O (2008) Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II. Hum Mutat 29(3):451. doi: 10.1002/humu.9524 PubMedCrossRefGoogle Scholar
  26. Estrada-Cuzcano A, Koenekoop RK, Senechal A, De Baere EB, de Ravel T, Banfi S, Kohl S, Ayuso C, Sharon D, Hoyng CB, Hamel CP, Leroy BP, Ziviello C, Lopez I, Bazinet A, Wissinger B, Sliesoraityte I, Avila-Fernandez A, Littink KW, Vingolo EM, Signorini S, Banin E, Mizrahi-Meissonnier L, Zrenner E, Kellner U, Collin RW, den Hollander AI, Cremers FP, Klevering BJ (2012) BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl syndrome. Arch Ophthalmol 130(11):1425–1432. doi: 10.1001/archophthalmol.2012.2434 PubMedCrossRefGoogle Scholar
  27. Eudy JD, Weston MD, Yao S, Hoover DM, Rehm HL, Ma-Edmonds M, Yan D, Ahmad I, Cheng JJ, Ayuso C, Cremers C, Davenport S, Moller C, Talmadge CB, Beisel KW, Tamayo M, Morton CC, Swaroop A, Kimberling WJ, Sumegi J (1998) Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa. Science 280(5370):1753–1757PubMedCrossRefGoogle Scholar
  28. Francois J (1971) Sex-linked chorioretinal heredodegenerations. Birth Defects Orig Artic Ser 7(3):99–116PubMedGoogle Scholar
  29. Fu Q, Wang F, Wang H, Xu F, Zaneveld JE, Ren H, Keser V, Lopez I, Tuan HF, Salvo JS, Wang X, Zhao L, Wang K, Li Y, Koenekoop RK, Chen R, Sui R (2013a) Next-generation sequencing-based molecular diagnosis of a Chinese patient cohort with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci 54(6):4158–4166. doi: 10.1167/iovs.13-11672 PubMedCentralPubMedCrossRefGoogle Scholar
  30. Fu W, O’Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, Gabriel S, Rieder MJ, Altshuler D, Shendure J, Nickerson DA, Bamshad MJ, Project NES, Akey JM (2013b) Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493(7431):216–220. doi: 10.1038/nature11690 PubMedCentralPubMedCrossRefGoogle Scholar
  31. Fujinami K, Lois N, Davidson AE, Mackay DS, Hogg CR, Stone EM, Tsunoda K, Tsubota K, Bunce C, Robson AG, Moore AT, Webster AR, Holder GE, Michaelides M (2013a) A longitudinal study of stargardt disease: clinical and electrophysiologic assessment, progression, and genotype correlations. Am J Ophthalmol 155(6):1075–1088 e1013. doi: 10.1016/j.ajo.2013.01.018 PubMedCrossRefGoogle Scholar
  32. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, Tsubota K, Webster AR, Moore AT, Allikmets R, Michaelides M (2013b) ABCA4 gene screening by next-generation sequencing in a British cohort. Invest Ophthalmol Vis Sci 54(10):6662–6674. doi: 10.1167/iovs.13-12570 PubMedCentralPubMedCrossRefGoogle Scholar
  33. Garber M, Guttman M, Clamp M, Zody MC, Friedman N, Xie X (2009) Identifying novel constrained elements by exploiting biased substitution patterns. Bioinformatics 25(12):i54–i62. doi: 10.1093/bioinformatics/btp190 PubMedCentralPubMedCrossRefGoogle Scholar
  34. Genomes Project C, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA (2010) A map of human genome variation from population-scale sequencing. Nature 467(7319):1061–1073. doi: 10.1038/nature09534 PubMedCrossRefGoogle Scholar
  35. Genomes Project C, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491(7422):56–65. doi: 10.1038/nature11632 PubMedCrossRefGoogle Scholar
  36. Green PM, Saad S, Lewis CM, Giannelli F (1999) Mutation rates in humans. I. Overall and sex-specific rates obtained from a population study of hemophilia B. Am J Hum Genet 65(6):1572–1579. doi: 10.1086/302651 PubMedCentralPubMedCrossRefGoogle Scholar
  37. Haim M (2002) Epidemiology of retinitis pigmentosa in Denmark. Acta Ophthalmol Scand Suppl 233:1–34PubMedCrossRefGoogle Scholar
  38. Siepel A, Pollard KS, Haussler D, RECOMB (2006) New methods for detecting lineage-specific selection. In: Proceedings of the 10th international conference on research in computational molecular biology, vol 3909. Springer, Berlin, pp 190–205Google Scholar
  39. Hoefele J, Sudbrak R, Reinhardt R, Lehrack S, Hennig S, Imm A, Muerb U, Utsch B, Attanasio M, O’Toole JF, Otto E, Hildebrandt F (2005) Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis. Hum Mutat 25(4):411. doi: 10.1002/humu.9326 PubMedCrossRefGoogle Scholar
  40. Jansen GA, Waterham HR, Wanders RJ (2004) Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Hum Mutat 23(3):209–218. doi: 10.1002/humu.10315 PubMedCrossRefGoogle Scholar
  41. Kajiwara K, Berson EL, Dryja TP (1994) Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264(5165):1604–1608PubMedCrossRefGoogle Scholar
  42. Kohn L, Kadzhaev K, Burstedt MS, Haraldsson S, Hallberg B, Sandgren O, Golovleva I (2007) Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families. Eur J Hum Genet 15(6):664–671. doi: 10.1038/sj.ejhg.5201817 PubMedCrossRefGoogle Scholar
  43. Kolehmainen J, Wilkinson R, Lehesjoki AE, Chandler K, Kivitie-Kallio S, Clayton-Smith J, Traskelin AL, Waris L, Saarinen A, Khan J, Gross-Tsur V, Traboulsi EI, Warburg M, Fryns JP, Norio R, Black GC, Manson FD (2004) Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet 75(1):122–127. doi: 10.1086/422197 PubMedCentralPubMedCrossRefGoogle Scholar
  44. Le Quesne Stabej P, Saihan Z, Rangesh N, Steele-Stallard HB, Ambrose J, Coffey A, Emmerson J, Haralambous E, Hughes Y, Steel KP, Luxon LM, Webster AR, Bitner-Glindzicz M (2012) Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. J Med Genet 49(1):27–36. doi: 10.1136/jmedgenet-2011-100468 PubMedCentralPubMedCrossRefGoogle Scholar
  45. Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M (1999) Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, Stargardt disease. Am J Hum Genet 64(2):422–434. doi: 10.1086/302251 PubMedCentralPubMedCrossRefGoogle Scholar
  46. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25(14):1754–1760. doi: 10.1093/bioinformatics/btp324 PubMedCentralPubMedCrossRefGoogle Scholar
  47. Lindblad-Toh K, Garber M, Zuk O, Lin MF, Parker BJ, Washietl S, Kheradpour P, Ernst J, Jordan G, Mauceli E, Ward LD, Lowe CB, Holloway AK, Clamp M, Gnerre S, Alfoldi J, Beal K, Chang J, Clawson H, Cuff J, Di Palma F, Fitzgerald S, Flicek P, Guttman M, Hubisz MJ, Jaffe DB, Jungreis I, Kent WJ, Kostka D, Lara M, Martins AL, Massingham T, Moltke I, Raney BJ, Rasmussen MD, Robinson J, Stark A, Vilella AJ, Wen J, Xie X, Zody MC, Broad Institute Sequencing P, Whole Genome Assembly T, Baldwin J, Bloom T, Chin CW, Heiman D, Nicol R, Nusbaum C, Young S, Wilkinson J, Worley KC, Kovar CL, Muzny DM, Gibbs RA, Baylor College of Medicine Human Genome Sequencing Center Sequencing T, Cree A, Dihn HH, Fowler G, Jhangiani S, Joshi V, Lee S, Lewis LR, Nazareth LV, Okwuonu G, Santibanez J, Warren WC, Mardis ER, Weinstock GM, Wilson RK, Genome Institute at Washington U, Delehaunty K, Dooling D, Fronik C, Fulton L, Fulton B, Graves T, Minx P, Sodergren E, Birney E, Margulies EH, Herrero J, Green ED, Haussler D, Siepel A, Goldman N, Pollard KS, Pedersen JS, Lander ES, Kellis M (2011) A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478 (7370):476–482. doi: 10.1038/nature10530
  48. Liu X, Jian X, Boerwinkle E (2013) dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations. Hum Mutat 34(9):E2393–E2402. doi: 10.1002/humu.22376 PubMedCentralPubMedCrossRefGoogle Scholar
  49. Maugeri A, van Driel MA, van de Pol DJ, Klevering BJ, van Haren FJ, Tijmes N, Bergen AA, Rohrschneider K, Blankenagel A, Pinckers AJ, Dahl N, Brunner HG, Deutman AF, Hoyng CB, Cremers FP (1999) The 2588G–>C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet 64(4):1024–1035PubMedCentralPubMedCrossRefGoogle Scholar
  50. McGee TL, Seyedahmadi BJ, Sweeney MO, Dryja TP, Berson EL (2010) Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. J Med Genet 47(7):499–506. doi: 10.1136/jmg.2009.075143 PubMedCentralPubMedCrossRefGoogle Scholar
  51. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303. doi: 10.1101/gr.107524.110 PubMedCentralPubMedCrossRefGoogle Scholar
  52. McLaughlin ME, Ehrhart TL, Berson EL, Dryja TP (1995) Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. Proc Natl Acad Sci 92(8):3249–3253PubMedCentralPubMedCrossRefGoogle Scholar
  53. Mokry M, Feitsma H, Nijman IJ, de Bruijn E, van der Zaag PJ, Guryev V, Cuppen E (2010) Accurate SNP and mutation detection by targeted custom microarray-based genomic enrichment of short-fragment sequencing libraries. Nucleic Acids Res 38(10):e116. doi: 10.1093/nar/gkq072 PubMedCentralPubMedCrossRefGoogle Scholar
  54. Najera C, Beneyto M, Blanca J, Aller E, Fontcuberta A, Millan JM, Ayuso C (2002) Mutations in myosin VIIA (MYO7A) and usherin (USH2A) in Spanish patients with Usher syndrome types I and II, respectively. Hum Mutat 20(1):76–77. doi: 10.1002/humu.9042 PubMedCrossRefGoogle Scholar
  55. Neveling K, Collin RW, Gilissen C, van Huet RA, Visser L, Kwint MP, Gijsen SJ, Zonneveld MN, Wieskamp N, de Ligt J, Siemiatkowska AM, Hoefsloot LH, Buckley MF, Kellner U, Branham KE, den Hollander AI, Hoischen A, Hoyng C, Klevering BJ, van den Born LI, Veltman JA, Cremers FP, Scheffer H (2012) Next-generation genetic testing for retinitis pigmentosa. Hum Mutat 33(6):963–972. doi: 10.1002/humu.22045 PubMedCentralPubMedCrossRefGoogle Scholar
  56. Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31(13):3812–3814PubMedCentralPubMedCrossRefGoogle Scholar
  57. Otto E, Hoefele J, Ruf R, Mueller AM, Hiller KS, Wolf MT, Schuermann MJ, Becker A, Birkenhager R, Sudbrak R, Hennies HC, Nurnberg P, Hildebrandt F (2002) A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet 71(5):1161–1167. doi: 10.1086/344395 PubMedCentralPubMedCrossRefGoogle Scholar
  58. Pennings RJ, Te Brinke H, Weston MD, Claassen A, Orten DJ, Weekamp H, Van Aarem A, Huygen PL, Deutman AF, Hoefsloot LH, Cremers FP, Cremers CW, Kimberling WJ, Kremer H (2004) USH2A mutation analysis in 70 Dutch families with Usher syndrome type II. Hum Mutat 24(2):185. doi: 10.1002/humu.9259 PubMedCrossRefGoogle Scholar
  59. Reva B, Antipin Y, Sander C (2011) Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 39(17):e118. doi: 10.1093/nar/gkr407 PubMedCentralPubMedCrossRefGoogle Scholar
  60. Rivera A, White K, Stohr H, Steiner K, Hemmrich N, Grimm T, Jurklies B, Lorenz B, Scholl HP, Apfelstedt-Sylla E, Weber BH (2000) A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet 67(4):800–813. doi: 10.1086/303090 PubMedCentralPubMedCrossRefGoogle Scholar
  61. Rivolta C, Sweklo EA, Berson EL, Dryja TP (2000) Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet 66(6):1975–1978. doi: 10.1086/302926 PubMedCentralPubMedCrossRefGoogle Scholar
  62. Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386PubMedGoogle Scholar
  63. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575–576. doi: 10.1038/nmeth0810-575 PubMedCrossRefGoogle Scholar
  64. Seyedahmadi BJ, Rivolta C, Keene JA, Berson EL, Dryja TP (2004) Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. Exp Eye Res 79(2):167–173. doi: 10.1016/j.exer.2004.03.005 PubMedCrossRefGoogle Scholar
  65. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29(1):308–311PubMedCentralPubMedCrossRefGoogle Scholar
  66. Shihab HA, Gough J, Cooper DN, Stenson PD, Barker GL, Edwards KJ, Day IN, Gaunt TR (2013) Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. Hum Mutat 34(1):57–65. doi: 10.1002/humu.22225 PubMedCentralPubMedCrossRefGoogle Scholar
  67. Shu X, Black GC, Rice JM, Hart-Holden N, Jones A, O’Grady A, Ramsden S, Wright AF (2007) RPGR mutation analysis and disease: an update. Hum Mutat 28(4):322–328. doi: 10.1002/humu.20461 PubMedCrossRefGoogle Scholar
  68. Simpson DA, Clark GR, Alexander S, Silvestri G, Willoughby CE (2011) Molecular diagnosis for heterogeneous genetic diseases with targeted high-throughput DNA sequencing applied to retinitis pigmentosa. J Med Genet 48(3):145–151. doi: 10.1136/jmg.2010.083568 PubMedCrossRefGoogle Scholar
  69. Song J, Smaoui N, Ayyagari R, Stiles D, Benhamed S, MacDonald IM, Daiger SP, Tumminia SJ, Hejtmancik F, Wang X (2011) High-throughput retina-array for screening 93 genes involved in inherited retinal dystrophy. Invest Ophthalmol Vis Sci 52(12):9053–9060. doi: 10.1167/iovs.11-7978 PubMedCentralPubMedCrossRefGoogle Scholar
  70. Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN (2013) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. doi: 10.1007/s00439-013-1358-4 PubMedGoogle Scholar
  71. Sun H, Smallwood PM, Nathans J (2000) Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet 26(2):242–246. doi: 10.1038/79994 PubMedCrossRefGoogle Scholar
  72. Tuson M, Marfany G, Gonzalez-Duarte R (2004) Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26). Am J Hum Genet 74(1):128–138. doi: 10.1086/381055 PubMedCentralPubMedCrossRefGoogle Scholar
  73. van den Hurk JA, Schwartz M, van Bokhoven H, van de Pol TJ, Bogerd L, Pinckers AJ, Bleeker-Wagemakers EM, Pawlowitzki IH, Ruther K, Ropers HH, Cremers FP (1997) Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene. Hum Mutat 9 (2):110–117. doi: 10.1002/(SICI)1098-1004(1997)9:2<110::AID-HUMU2>3.0.CO;2-D
  74. Venturini G, Di Gioia SA, Harper S, Weigel-Difranco C, Rivolta C, Berson EL (2014) Molecular genetics of FAM161A in North American patients with early-onset retinitis pigmentosa. PLoS One 9(3):e92479. doi: 10.1371/journal.pone.0092479 PubMedCentralPubMedCrossRefGoogle Scholar
  75. Wada Y, Tada A, Itabashi T, Kawamura M, Sato H, Tamai M (2005) Screening for mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa. Am J Ophthalmol 140(1):163–165. doi: 10.1016/j.ajo.2005.01.017 PubMedCrossRefGoogle Scholar
  76. Wanders RJA, Waterham HR, Leroy BP (1993) Refsum Disease. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K (eds) GeneReviews. SeattleGoogle Scholar
  77. Wang DY, Chan WM, Tam PO, Baum L, Lam DS, Chong KK, Fan BJ, Pang CP (2005) Gene mutations in retinitis pigmentosa and their clinical implications. Clin Chim Acta 351(1–2):5–16. doi: 10.1016/j.cccn.2004.08.004 PubMedCrossRefGoogle Scholar
  78. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164. doi: 10.1093/nar/gkq603 PubMedCentralPubMedCrossRefGoogle Scholar
  79. Wang X, Wang H, Sun V, Tuan HF, Keser V, Wang K, Ren H, Lopez I, Zaneveld JE, Siddiqui S, Bowles S, Khan A, Salvo J, Jacobson SG, Iannaccone A, Wang F, Birch D, Heckenlively JR, Fishman GA, Traboulsi EI, Li Y, Wheaton D, Koenekoop RK, Chen R (2013) Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. J Med Genet 50(10):674–688. doi: 10.1136/jmedgenet-2013-101558 PubMedCentralPubMedCrossRefGoogle Scholar
  80. Wang F, Wang H, Tuan HF, Nguyen DH, Sun V, Keser V, Bowne SJ, Sullivan LS, Luo H, Zhao L, Wang X, Zaneveld JE, Salvo JS, Siddiqui S, Mao L, Wheaton DK, Birch DG, Branham KE, Heckenlively JR, Wen C, Flagg K, Ferreyra H, Pei J, Khan A, Ren H, Wang K, Lopez I, Qamar R, Zenteno JC, Ayala-Ramirez R, Buentello-Volante B, Fu Q, Simpson DA, Li Y, Sui R, Silvestri G, Daiger SP, Koenekoop RK, Zhang K, Chen R (2014) Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet 133(3):331–345. doi: 10.1007/s00439-013-1381-5 PubMedCrossRefGoogle Scholar
  81. Webster AR, Heon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT, Beck G, Fishman GA, Lam BL, Levin A, Heckenlively JR, Jacobson SG, Weleber RG, Sheffield VC, Stone EM (2001) An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci 42(6):1179–1189PubMedGoogle Scholar
  82. Wiszniewski W, Zaremba CM, Yatsenko AN, Jamrich M, Wensel TG, Lewis RA, Lupski JR (2005) ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. Hum Mol Genet 14(19):2769–2778. doi: 10.1093/hmg/ddi310 PubMedCrossRefGoogle Scholar
  83. Zeitz C, Labs S, Lorenz B, Forster U, Uksti J, Kroes HY, De Baere E, Leroy BP, Cremers FP, Wittmer M, van Genderen MM, Sahel JA, Audo I, Poloschek CM, Mohand-Said S, Fleischhauer JC, Huffmeier U, Moskova-Doumanova V, Levin AV, Hamel CP, Leifert D, Munier FL, Schorderet DF, Zrenner E, Friedburg C, Wissinger B, Kohl S, Berger W (2009) Genotyping microarray for CSNB-associated genes. Invest Ophthalmol Vis Sci 50(12):5919–5926. doi: 10.1167/iovs.09-3548 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Li Zhao
    • 1
    • 2
  • Feng Wang
    • 2
    • 3
  • Hui Wang
    • 2
    • 3
  • Yumei Li
    • 2
    • 3
  • Sharon Alexander
    • 4
  • Keqing Wang
    • 2
    • 3
  • Colin E. Willoughby
    • 5
  • Jacques E. Zaneveld
    • 2
    • 3
  • Lichun Jiang
    • 2
    • 3
  • Zachry T. Soens
    • 2
    • 3
  • Philip Earle
    • 4
  • David Simpson
    • 4
  • Giuliana Silvestri
    • 4
    Email author
  • Rui Chen
    • 1
    • 2
    • 3
    Email author
  1. 1.Structural and Computational Biology and Molecular BiophysicsBaylor College of MedicineHoustonUSA
  2. 2.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  3. 3.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  4. 4.Centre for Experimental MedicineQueen’s University Belfast, Clinical ICS-ABelfastUK
  5. 5.Department of Eye and Vision Science, Institute of Ageing and Chronic DiseaseUniversity of LiverpoolLiverpoolUK

Personalised recommendations