Leber Congenital Amaurosis in Asia

  • Sharola Dharmaraj
  • Anshuman Verma
  • P. Sundaresan
  • Chitra Kannabiran
Part of the Essentials in Ophthalmology book series (ESSENTIALS)


Leber congenital amaurosis (LCA) is a heterogeneous infantile retinal dystrophy presenting with severe visual loss, nystagmus, sluggish pupillary responses and an extinguished electroretinogram (ERG). LCA accounts for 5% of inherited retinal degenerative disorders worldwide. To date at least 30 genes are known to either cause or be associated with this condition. The genes perform a structural or functional role in the visual pathway. Mutations in several of these genes causing LCA have been identified in Asian populations (AIPL1, ALMS1, CABP4, CCT2, CEP290, CLUAP1, CRB1, CNGA3, CRX, CTNNA1, CYP4V2, GDF6, GUCY2D, IFT140, IMPDH1, IQCB1, KCNJ13, LCA5, LRAT, MERTK, MYO7A, NMNAT1, OTX2, PEX1, PNPLA6, POC1, PRPH2, RD3, RDH12, RPE65, RPGRIP1, SPATA7 and TULP1). An increased rate of consanguinity in some Asian populations has been noted, and gene identification using homozygosity mapping and testing for common mutations is possible, but the prevalence of mutations is not always identical to cohorts in the Western world. The advent of next-generation, whole genome and exome sequencing in addition to gene chip technology have revolutionised genetic and molecular diagnosis. Phenotype-genotype correlation of this disorder in some instances has made the choice of laboratory diagnosis rapid and easier. An accurate genetic diagnosis has become mandatory to access upcoming treatment options. Gene therapy for LCA has been encouraging recently as shown in the clinical trials involving RPE65-related LCA both in canines and humans.


LCA RPE65 Clinical trials Gene therapy Consanguinity Mutations Asian Heterogeneity Genotype Phenotype Treatment Sequencing AIPL1 ALMS1 CABP4 CCT2 CEP290 CLUAP1 CRB1 CNGA3 CRX CTNNA1 CYP4V2 GDF6 GUCY2D IFT140 IMPDH1 IQCB1 KCNJ13 LCA5 LRAT MERTK MYO7A NMNAT1 OTX2 PEX1 PNPLA6 POC1 PRPH2 RD3 RDH12 RPE65 RPGRIP1 SPATA7 TULP1 



The authors would like to thank Desta Bokre of the Institute of Ophthalmology Library UCL, London UK for helping with the bibliography and references.

Compliance with Ethical Requirements

All authors declare that he/she has no conflict of interest.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

No animal or human studies were carried out by the authors for this article.


  1. 1.
    Leber T. Ueber Retinitis Pigmentosa und angeborene amaurose. Graefes Arch Clin Exp Ophthalmol. 1869;15:1–25.CrossRefGoogle Scholar
  2. 2.
    Franceschetti A, Dieterle P. Diagnostic and prognostic importance of the electroretinogram in tapetoretinal degeneration with reduction of the visual field and hemeralopia. Confin Neurol. 1954;14:184.CrossRefPubMedGoogle Scholar
  3. 3.
    Camuzat A, Rozet JM, Dollfus H, Gerber S, Perrault I, Bonneau D, Ghazi I, Dufier JL, Munnich A, Kaplan J. Evidence for genetic heterogeneity in Leber’s congenital amaurosis and fine mapping of LCA1 to chromosome 17P13. Invest Ophthalmol Vis Sci. 1996;37:4585.Google Scholar
  4. 4.
    Dandona R, Dandona L. Childhood blindness in India: a population based perspective. Br J Ophthalmol. 2003;87:263–5.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kaplan J, Bonneau D, Frézal J, Munnich A, Dufier J-L. Clinical and genetic heterogeneity in retinitis Pigmentosa. Hum Genet. 1990;85:635–42.CrossRefPubMedGoogle Scholar
  6. 6.
    Bunker CH, Berson EL, Bromley WC, Hayes RP, Roderick TH. Prevalence of retinitis Pigmentosa in Maine. Am J Ophthalmol. 1984;97:357–65.CrossRefGoogle Scholar
  7. 7.
    Kumaramanickavel G, Joseph B, Vidhya A, Arokiasamy T, Shridhara Shetty N. Consanguinity and ocular genetic diseases in South India: analysis of a five-year study. Community Genet. 2002;5:182–5.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gilbert C, Foster A. Childhood blindness in the context of VISION 2020 – the right to sight. Bull World Health Organ. 2001;79:227–32.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Bagchi K, Bhattacharya S. The profile of visual loss in children--a retrospective study in a referral hospital in India. J Indian Med Assoc. 2006;104(366):368–70.Google Scholar
  10. 10.
    Perrault I, Hanein S, Gerber S, Barbet F, Dufier JL, Munnich A, Rozet JM, Kaplan J. Evidence of autosomal dominant leber congenital amaurosis (LCA) underlain by a CRX heterozygous null allele. J Med Genet. 2003;40:E90.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rivolta C, Berson EL, Dryja TP. Dominant leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX. Hum Mutat. 2001;18:488–98.CrossRefGoogle Scholar
  12. 12.
    Sohocki MM, Sullivan LS, Mintz-Hittner HA, Birch D, Heckenlively JR, Freund CL, Mcinnes RR, Daiger SP. A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. Am J Hum Genet. 1998;63:1307–15.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Inglehearn CF. Molecular genetics of human retinal dystrophies. Eye (Lond). 1998;12(Pt 3B):571–9.CrossRefGoogle Scholar
  14. 14.
    Rattner A, Sun H, Nathans J. Molecular genetics of human retinal disease. Annu Rev Genet. 1999;33:89–131.CrossRefGoogle Scholar
  15. 15.
    Cideciyan AV, Hood DC, Huang Y, Banin E, Li ZY, Stone EM, Milam AH, Jacobson SG. Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man. Proc Natl Acad Sci U S A. 1998;95:7103–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Milam AH, Li ZY, Fariss RN. Histopathology of the human retina in retinitis pigmentosa. Prog Retin Eye Res. 1998;17:175–205.CrossRefGoogle Scholar
  17. 17.
    Mohand-Said S, Hicks D, Leveillard T, Picaud S, Porto F, Sahel JA. Rod-cone interactions: developmental and clinical significance. Prog Retin Eye Res. 2001;20:451–67.CrossRefGoogle Scholar
  18. 18.
    Fazzi E, Lanners J, Danova S, Ferrarri-Ginevra O, Gheza C, Luparia A, Balottin U, Lanzi G. Stereotyped behaviours in blind children. Brain Dev. 1999;21:522–8.CrossRefGoogle Scholar
  19. 19.
    Fazzi E, Signorini SG, Uggetti C, Bianchi PE, Lanners J, Lanzi G. Towards improved clinical characterization of Leber congenital amaurosis: neurological and systemic findings. Am J Med Genet A. 2005;132A:13–9.CrossRefGoogle Scholar
  20. 20.
    Grieshaber MC, Niemeyer G. Leber’s congenital amaurosis: diagnosis, course and differential diagnosis. Klinische Monatsblatter Fur Augenheilkunde. 1998;212:309–10.CrossRefGoogle Scholar
  21. 21.
    Fazzi E, Signorini SG, Scelsa B, Bova SM, Lanzi G. Leber’s congenital amaurosis: an update. Eur J Paediatr Neurol. 2003;7:13–22.CrossRefGoogle Scholar
  22. 22.
    Francois J. Leber’s congenital tapetoretinal degeneration. Int Ophthalmol Clin. 1968;8:929–47.CrossRefGoogle Scholar
  23. 23.
    Heher KL, Traboulsi EI, Maumenee IH. The natural history of Leber’s congenital amaurosis: age-related findings in 35 patients. Ophthalmology. 1992;99:241–5.CrossRefGoogle Scholar
  24. 24.
    Elder MJ. Leber congenital amaurosis and its association with keratoconus and keratoglobus. J Pediatr Ophthalmol Strabismus. 1994;31:38–40.PubMedGoogle Scholar
  25. 25.
    Stoiber J, Muss WH, Ruckhofer J, Thaller-Antlanger H, Alzner E, Grabner G. Recurrent keratoconus in a patient with Leber congenital amaurosis. Cornea. 2000;19:395–8.CrossRefGoogle Scholar
  26. 26.
    Dharmaraj S, Leroy BP, Sohocki MM, Koenekoop RK, Perrault I, Anwar K, Khaliq S, Devi RS, Birch DG, De Pool E, Izquierdo N, Van Maldergem L, Ismail M, Payne AM, Holder GE, Bhattacharya SS, Bird AC, Kaplan J, Maumenee IH. The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations. Arch Ophthalmol. 2004;122:1029–37.CrossRefGoogle Scholar
  27. 27.
    Schroeder R, Mets MB, Maumenee IH. Leber’s congenital amaurosis. Retrospective review of 43 cases and a new fundus finding in two cases. Arch Ophthalmol. 1987;105:356–9.CrossRefGoogle Scholar
  28. 28.
    Wagner RS, Caputo AR, Nelson LB, Zanoni D. High hyperopia in Leber’s congenital amaurosis. Arch Ophthalmol. 1985;103:1507–9.CrossRefGoogle Scholar
  29. 29.
    Lotery AJ, Namperumalsamy P, Jacobson SG, Weleber RG, Fishman GA, Musarella MA, Hoyt CS, Heon E, Levin A, Jan J, Lam B, Carr RE, Franklin A, Radha S, Andorf JL, Sheffield VC, Stone EM. Mutation analysis of 3 genes in patients with Leber congenital amaurosis. Arch Ophthalmol. 2000;118:538–43.CrossRefGoogle Scholar
  30. 30.
    Sonksen PM, Dale N. Visual impairment in infancy: impact on neurodevelopmental and neurobiological processes. Dev Med Child Neurol. 2002;44:782–91.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Galvin JA, Fishman GA, Stone EM, Koenekoop RK. Clinical phenotypes in carriers of leber congenital amaurosis mutations. Ophthalmology. 2005a;112:349–56.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kriss A, Russell-Eggit I. Electrophysiological assessment of visual pathway function in infants. Eye. 1992;6:145–53.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ellis DS, Heckenlively JR, Martin CL, Lachman RS, Sakati NA, Rimoin DL. Leber’s congenital amaurosis associated with familial juvenile Nephronophthisis and cone-shaped epiphyses of the hands (The Saldino-Mainzer syndrome). Am J Ophthalmol. 1984;97:233–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Løken AC, Hanssen O, Halvorsen S, Jølster NJ. Hereditary renal dysplasia and blindness. Acta Paediatr. 1961;50:177–84.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ivarsson SA, Bjerre I, Brun A, Ljungberg O, Maly E, Taylor I. Joubert syndrome associated with Leber amaurosis and multicystic kidneys. Am J Med Genet. 1993;45:542–7.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Russell-Eggitt IM, Clayton PT, Coffey R, Kriss A, Taylor DSI, Taylor JFN. Alstrom syndrome – report of 22 cases and literature review. Ophthalmology. 1998;105:1274–80.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mendley SR, Poznanski AK, Spargo BH, Langman CB. Hereditary sclerosing glomerulopathy in the conorenal syndrome. Am J Kidney Dis. 1995;25:792–7.CrossRefGoogle Scholar
  38. 38.
    Gleeson JG, Keeler LC, Parisi MA, Marsh SE, Chance PF, Glass IA, Graham JM, Maria BL, Barkovich AJ, Dobyns WB. Molar tooth sign of the midbrain-hindbrain junction: occurrence in multiple distinct syndromes. Am J Med Genet A. 2004;125A:125–34.CrossRefGoogle Scholar
  39. 39.
    Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F. The Centrosomal protein Nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet. 2006;38:674–81.CrossRefGoogle Scholar
  40. 40.
    Den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, Van Den Born LI, Rohrschneider K, Cremers FP. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006;79:556–61.CrossRefGoogle Scholar
  41. 41.
    Bibb LC, Holt JKL, Tarttelin EE, Hodges MD, Gregory-Evans K, Rutherford A, Lucas RJ, Sowden JC, Gregory-Evans CY. Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets. Critical differences during human and mouse eye development. Hum Mol Genet. 2001;10:1571–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Porto FBO, Perrault I, Hicks D, Rozet JM, Hanoteau N, Hanein S, Kaplan J, Sahel JA. Prenatal human ocular degeneration occurs in Leber’s congenital amaurosis (LCA2). J Gene Med. 2002;4:390–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Aguirre GD, Baldwin V, Pearce-Kelling S, Narfström K, Ray K, Acland GM. Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect. Mol Vis. 1998;4:23.PubMedGoogle Scholar
  44. 44.
    Heegaard S, Rosenberg T, Preising M, Prause JU, Bek T. An unusual retinal vascular morphology in connection with a novel AIPL1 mutation in Leber’s congenital amaurosis. Br J Ophthalmol. 2003;87:980–3.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Porto FBO, Perrault I, Hicks D, Rozet JM, Hanoteau N, Hanein S, Kaplan J, Sahel JA. Prenatal human ocular degeneration occurs in Leber’s congenital amaurosis. In: Lavail MM, Hollyfield JG, Anderson RE, editors. Retinal degenerations: mechanisms and experimental therapy. Boston: Springer; 2003.Google Scholar
  46. 46.
    Den Hollander AI, Roepman R, Koenekoop RK, Cremers FPM. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res. 2008;27:391–419.CrossRefGoogle Scholar
  47. 47.
    Srikrupa NN, Srilekha S, Sen P, Arokiasamy T, Swaminathan M, Bhende M, Kapur S, Soumittra N. Genetic profile and mutation spectrum of Leber congenital amaurosis in a larger Indian Cohort using high throughput targeted re-sequencing. Clin Genet. 2017;93(2):329–39.CrossRefGoogle Scholar
  48. 48.
    Coppieters F, Casteels I, Meire F, De Jaegere S, Hooghe S, Van Regemorter N, Van Esch H, Matuleviciene A, Nunes L, Meersschaut V, Walraedt S, Standaert L, Coucke P, Hoeben H, Kroes HY, Vande Walle J, De Ravel T, Leroy BP, De Baere E. Genetic screening of Lca in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes. Hum Mutat. 2010;31:E1709–66.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kaplan J. Leber congenital amaurosis: from darkness to spotlight. Ophthalmic Genet. 2008;29:92–8.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sundaresan P, Vijayalakshmi P, Thompson S, Ko AC, Fingert JH, Stone EM. Mutations that are a common cause of Leber congenital amaurosis in northern America are rare in Southern India. Mol Vis. 2009;15:1781–7.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Wang X, Wang H, Cao M, Li Z, Chen X, Patenia C, Gore A, Abboud EB, Al-Rajhi AA, Lewis RA, Lupski JR, Mardon G, Zhang K, Muzny D, Gibbs RA, Chen R. Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. Hum Mutat. 2011;32:1450–9.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Friedman JS, Chang B, Kannabiran C, Chakarova C, Singh HP, Jalali S, Hawes NL, Branham K, Othman M, Filippova E, Thompson DA, Webster AR, Andreasson S, Jacobson SG, Bhattacharya SS, Heckenlively JR, Swaroop A. Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet. 2006;79:1059–70.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Perrault I, Estrada-Cuzcano A, Lopez I, Kohl S, Li S, Testa F, Zekveld-Vroon R, Wang X, Pomares E, Andorf J, Aboussair N, Banfi S, Delphin N, Den Hollander AI, Edelson C, Florijn R, Jean-Pierre M, Leowski C, Megarbane A, Villanueva C, Flores B, Munnich A, Ren H, Zobor D, Bergen A, Chen R, Cremers FP, Gonzalez-Duarte R, Koenekoop RK, Simonelli F, Stone E, Wissinger B, Zhang Q, Kaplan J, Rozet JM. Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype. PLoS One. 2013;8:E51622.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Astuti GD, Bertelsen M, Preising MN, Ajmal M, Lorenz B, Faradz SM, Qamar R, Collin RW, Rosenberg T, Cremers FP. Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark. Eur J Hum Genet. 2016;24:1071–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Li Y, Wang H, Peng J, Gibbs RA, Lewis RA, Lupski JR, Mardon G, Chen R. Mutation survey of known LCA genes and loci in the Saudi Arabian population. Invest Ophthalmol Vis Sci. 2009;50:1336–43.CrossRefPubMedGoogle Scholar
  56. 56.
    Sitorus RS, Lorenz B, Preising MN. Analysis of three genes in Leber congenital amaurosis in Indonesian patients. Vis Res. 2003;43:3087–93.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang H, Wang X, Zou X, Xu S, Li H, Soens ZT, Wang K, Li Y, Dong F, Chen R, Sui R. Comprehensive molecular diagnosis of a large Chinese Leber congenital amaurosis cohort. Invest Ophthalmol Vis Sci. 2015;56:3642–55.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Hosono K, Harada Y, Kurata K, Hikoya A, Sato M, Minoshima S, Hotta Y. Novel GUCY2D gene mutations in Japanese male twins with Leber congenital amaurosis. J Ophthalmol. 2015;2015:693468.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Verma A, Perumalsamy V, Shetty S, Kulm M, Sundaresan P. Mutational screening of LCA genes emphasizing RPE65 in South Indian cohort of patients. PLoS One. 2013;8:E73172.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Srilekha S, Arokiasamy T, Srikrupa NN, Umashankar V, Meenakshi S, Sen P, Kapur S, Soumittra N. Homozygosity mapping in Leber congenital amaurosis and autosomal recessive retinitis pigmentosa in South Indian families. PLoS One. 2015;10:E0131679.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Chen YB, Zhang QY, Shen T, Xiao XS, Li SQ, Guan LP, Zhang JG, Zhu ZH, Yin Y, Wang PF, Guo XM, Wang J, Zhang QJ. Comprehensive mutation analysis by whole-exome sequencing in 41 Chinese families with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2013;54:4351–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Gradstein L, Zolotushko J, Sergeev YV, Lavy I, Narkis G, Perez Y, Guigui S, Sharon D, Banin E, Walter E, Lifshitz T, Birk OS. Novel GUCY2D mutation causes phenotypic variability of Leber congenital amaurosis in a large kindred. BMC Med Genet. 2016;17:52.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Li L, Xiao XS, Li SQ, Jia XY, Wang PF, Guo XM, Jiao XD, Zhang QJ, Hejtmancik JF. Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis. Plos One. 2011;6:e19458.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Katagiri S, Hayashi T, Kondo M, Tsukitome H, Yoshitake K, Akahori M, Ikeo K, Tsuneoka H, Iwata T. RPE65 mutations in two Japanese families with Leber congenital amaurosis. Ophthalmic Genet. 2016;37:161–9.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Wada Y, Tamai M. Leber’s congenital amaurosis with RPE65 gene mutation. Jpn J Clin Ophthalmol. 2001;55:401–3.Google Scholar
  66. 66.
    Mckay GJ, Clarke S, Davis JA, Simpson DAC, Silvestri G. Pigmented paravenous chorioretinal atrophy is associated with a mutation within the crumbs homolog 1 (CRB1) gene. Invest Ophthalmol Vis Sci. 2005;46:322–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Mckibbin M, Ali M, Mohamed MD, Booth AP, Bishop F, Pal B, Springell K, Raashid Y, Jafri H, Inglehearn CF. Genotype-phenotype correlation for Leber congenital amaurosis in Northern Pakistan. Arch Ophthalmol. 2010;128:107–13.CrossRefPubMedGoogle Scholar
  68. 68.
    Suzuki T, Fujimaki T, Yanagawa A, Arai E, Fujiki K, Wada Y, Murakami A. A novel exon 17 deletion mutation of RPGRIP1 gene in two siblings with Leber congenital amaurosis. Jpn J Ophthalmol. 2014;58:528–35.CrossRefPubMedGoogle Scholar
  69. 69.
    Nakamura M, Ito S, Miyake Y. Novel de novo mutation in CRX gene in a Japanese patient with Leber congenital amaurosis. Am J Ophthalmol. 2002;134:465–7.CrossRefPubMedGoogle Scholar
  70. 70.
    Beryozkin A, Shevah E, Kimchi A, Mizrahi-Meissonnier L, Khateb S, Ratnapriya R, Lazar CH, Blumenfeld A, Ben-Yosef T, Hemo Y, Pe'Er J, Averbuch E, Sagi M, Boleda A, Gieser L, Zlotogorski A, Falik-Zaccai T, Alimi-Kasem O, Jacobson SG, Chowers I, Swaroop A, Banin E, Sharon D. Whole exome sequencing reveals mutations in known retinal disease genes in 33 out of 68 Israeli families with inherited retinopathies. Sci Rep. 2015;5:13187.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Kuniyoshi K, Ikeo K, Sakuramoto H, Furuno M, Yoshitake K, Hatsukawa Y, Nakao A, Tsunoda K, Kusaka S, Shimomura Y, Iwata T. Novel nonsense and splice site mutations in CRB1 gene in two Japanese patients with early-onset retinal dystrophy. Doc Ophthalmol. 2015;130:49–55.CrossRefPubMedGoogle Scholar
  72. 72.
    Imani S, Cheng J, Mobasher-Jannat A, Wei C, Fu S, Yang L, Jadidi K, Khosravi MH, Mohazzab-Torabi S, Shasaltaneh MD, Li Y, Chen R, Fu J. Identification of a novel RPGRIP1 mutation in an Iranian family with Leber congenital amaurosis by exome sequencing. J Cell Mol Med. 2017;22(3):1733–42.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Huang H, Wang Y, Chen H, Chen Y, Wu J, Chiang PW, Fan N, Su Y, Deng J, Chen D, Li Y, Zhang X, Zhang M, Liang S, Banerjee S, Qi M, Liu X. Targeted next generation sequencing identified novel mutations in RPGRIP1 associated with both retinitis Pigmentosa and Leber’s congenital amaurosis in unrelated Chinese patients. Oncotarget. 2017;8:35176–83.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Li Y, Pan Q, Gu YS. Phenotype-genotype correlation with Sanger sequencing identified retinol dehydrogenase 12 (RDH12) compound heterozygous variants in a Chinese family with Leber congenital amaurosis. J Zhejiang Univ Sci B. 2017;18:421–9.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Ramamurthy V, Roberts M, Van Den Akker F, Niemi G, Reh TA, Hurley JB. AIPL1, a protein implicated in Leber’s congenital amaurosis, interacts with and aids in processing of farnesylated proteins. Proc Natl Acad Sci U S A. 2003;100:12630–5.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Sohocki MM, Bowne SJ, Sullivan LS, Blackshaw S, Cepko CL, Payne AM, Bhattacharya SS, Khaliq S, Mehdi SQ, Birch DG, Harrison WR, Elder FFB, Heckenlively JR, Daiger SP. Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nat Genet. 2000;24:79–83.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Van Der Spuy J, Chapple JP, Clark BJ, Luthert PJ, Sethi CS, Cheetham ME. The Leber congenital amaurosis gene product AIPL1 is localized exclusively in rod photoreceptors of the adult human retina. Hum Mol Genet. 2002;11:823–31.CrossRefPubMedGoogle Scholar
  78. 78.
    Gallon VA, Wilkie SE, Deery EC, Newbold RJ, Sohocki MM, Bhattacharya SS, Hunt DM, Warren MJ. Purification, characterisation and intracellular localisation of aryl hydrocarbon interacting protein-like 1 (AIPL1) and effects of mutations associated with inherited retinal dystrophies. Biochim Biophys Acta. 2004;1690:141–9.CrossRefPubMedGoogle Scholar
  79. 79.
    Van Der Spuy J, Munro PM, Luthert PJ, Preising MN, Bek T, Heegaard S, Cheetham ME. Predominant rod photoreceptor degeneration in Leber congenital amaurosis. Mol Vis. 2005;11:542–53.PubMedGoogle Scholar
  80. 80.
    Aboshiha J, Dubis AM, Van Der Spuy J, Nishiguchi KM, Cheeseman EW, Ayuso C, Ehrenberg M, Simonelli F, Bainbridge JW, Michaelides M. Preserved outer retina in AIPL1 Leber'S congenital amaurosis: implications for gene therapy. Ophthalmology. 2015;122:862–4.CrossRefPubMedGoogle Scholar
  81. 81.
    Li Y, Xu K, Zhang XH, Xie Y, Jiang F, Liu LJ. Comprehensive molecular screening in a cohort of Chinese patients with Leber congenital amaurosis or severe early childhood onset retinal dystrophy. Invest Ophthalmol Vis Sci. 2016;57:6180–7.CrossRefGoogle Scholar
  82. 82.
    Abu Safieh L, Al-Otaibi HM, Lewis RA, Kozak I. Novel mutations in two Saudi patients with congenital retinal dystrophy. Middle East Afr J Ophthalmol. 2016;23:139–41.CrossRefGoogle Scholar
  83. 83.
    Minegishi Y, Sheng X, Yoshitake K, Sergeev Y, Iejima D, Shibagaki Y, Monma N, Ikeo K, Furuno M, Zhuang W, Liu Y, Rong W, Hattori S, Iwata T. CCT2 mutations evoke Leber congenital amaurosis due to chaperone complex instability. Sci Rep. 2016;6:33742.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Jacobson SG, Cideciyan AV, Sumaroka A, Roman AJ, Charng J, Lu M, Choi W, Sheplock R, Swider M, Kosyk MS, Schwartz SB, Stone EM, Fishman GA. Outcome measures for clinical trials of Leber congenital amaurosis caused by the intronic mutation in the CEP290 gene. Invest Ophthalmol Vis Sci. 2017;58:2609–22.CrossRefPubMedGoogle Scholar
  85. 85.
    Perrault I, Delphin N, Hanein S, Gerber S, Dufier JL, Roche O, Defoort-Dhellemmes S, Dollfus H, Fazzi E, Munnich A, Kaplan J, Rozet JM. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat. 2007;28:416.CrossRefPubMedGoogle Scholar
  86. 86.
    Jacobson SG, Cideciyan AV, Huang WC, Sumaroka A, Nam HJ, Sheplock R, Schwartz SB. Leber congenital amaurosis: genotypes and retinal structure phenotypes. Adv Exp Med Biol. 2016;854:169–75.CrossRefPubMedGoogle Scholar
  87. 87.
    Frank V, Den Hollander AI, Bruchle NO, Zonneveld MN, Nurnberg G, Becker C, Du Bois G, Kendziorra H, Roosing S, Senderek J, Nurnberg P, Cremers FP, Zerres K, Bergmann C. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. Hum Mutat. 2008;29:45–52.CrossRefPubMedGoogle Scholar
  88. 88.
    Mcewen DP, Koenekoop RK, Khanna H, Jenkins PM, Lopez I, Swaroop A, Martens JR. Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons. Proc Natl Acad Sci U S A. 2007;104:15917–22.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Johnston JJ, Lee C, Wentzensen IM, Parisi MA, Crenshaw MM, Sapp JC, Gross JM, Wallingford JB, Biesecker LG. Compound heterozygous alterations in Intraflagellar transport protein CLUAP1 in a child with a novel Joubert and oral-facial-digital overlap syndrome. Cold Spring Harb Mol Case Stud. 2017;3:a001321.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Soens ZT, Li Y, Zhao L, Eblimit A, Dharmat R, Li Y, Chen Y, Naqeeb M, Fajardo N, Lopez I, Sun Z, Koenekoop RK, Chen R. Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1. Genet Med. 2016;18(10):1044–51.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    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. Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat Genet. 1999;23:217–21.CrossRefGoogle Scholar
  92. 92.
    Mehalow AK, Kameya S, Smith RS, Hawes NL, Denegre JM, Young JA, Bechtold L, Haider NB, Tepass U, Heckenlively JR, Chang B, Naggert JK, Nishina PM. CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Hum Mol Genet. 2003;12:2179–89.CrossRefPubMedGoogle Scholar
  93. 93.
    Van De Pavert SA, Kantardzhieva A, Malysheva A, Meuleman J, Versteeg I, Levelt C, Klooster J, Geiger S, Seeliger MW, Rashbass P, Le Bivic A, Wijnholds J. Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure. J Cell Sci. 2004;117:4169–77.CrossRefPubMedGoogle Scholar
  94. 94.
    Den Hollander AI, Ghiani M, De Kok YJM, Wijnholds J, Ballabio A, Cremers FPM, Broccoli V. Isolation of CRB1, a mouse homologue of Drosophila crumbs, and analysis of its expression pattern in eye and brain. Mech Dev. 2001a;110:203–7.CrossRefGoogle Scholar
  95. 95.
    Gerber S, Perrault I, Hanein S, Shalev S, Zlotogora J, Barbet F, Ducroq D, Dufier J, Munnich A, Rozet J, Kaplan J. A novel mutation disrupting the cytoplasmic domain of CRB1 in a large consanguineous family of Palestinian origin affected with Leber congenital amaurosis. Ophthalmic Genet. 2002;23:225–35.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Khaliq S, Abid A, Hameed A, Anwar K, Mohyuddin A, Azmat Z, Shami SA, Ismail M, Mehdi SQ. Mutation screening of Pakistani families with congenital eye disorders. Exp Eye Res. 2003;76:343–8.CrossRefPubMedGoogle Scholar
  97. 97.
    Lotery AJ, Jacobson SG, Fishman GA, Weleber RG, Fulton AB, Namperumalsamy P, Heon E, Levin AV, Grover S, Rosenow JR, Kopp KK, Sheffield VC, Stone EM. Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch Ophthalmol. 2001;119:415–20.CrossRefPubMedGoogle Scholar
  98. 98.
    Den Hollander AI, Heckenlively JR, Ingeborgh Van Den Born L, De Kok YJM, Van Der Velde-Visser SD, Kellner U, Jurklies B, Van Schooneveld MJ, Blankenagel A, Rohrschneider K, Wissinger B, Cruysberg JRM, Deutman AF, Brunner HG, Apfelstedt-Sylla E, Hoyng CB, Cremers FPM. Leber congenital amaurosis and retinitis pigmentosa with coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. Am J Hum Genet. 2001b;69:198–203.CrossRefPubMedCentralGoogle Scholar
  99. 99.
    Abouzeid H, Li Y, Maumenee IH, Dharmaraj S, Sundin O. A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis. Ophthalmic Genet. 2006;27:15–20.CrossRefPubMedGoogle Scholar
  100. 100.
    Jacobson SG, Cideciyan AV, Aleman TS, Pianta MJ, Sumaroka A, Schwartz SB, Smilko EE, Milam AH, Sheffield VC, Stone EM. Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Hum Mol Genet. 2003;12:1073–8.CrossRefGoogle Scholar
  101. 101.
    Simeone A, Gulisano M, Acampora D, Stornaiuolo A, Rambaldi M, Boncinelli E. Two vertebrate Homeobox genes related to the Drosophila empty spiracles gene are expressed in the embryonic cerebral cortex. EMBO J. 1992;11:2541–50.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Furukawa T, Morrow EM, Cepko CL. Crx, a novel Otx-like Homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell. 1997;91:531–41.CrossRefGoogle Scholar
  103. 103.
    Freund CL, Gregoryevans CY, Furukawa T, Papaioannou M, Looser J, Ploder L, Bellingham J, Ng D, Herbrick JAS, Duncan A, Scherer SW, Tsui LC, Loutradisanagnostou A, Jacobson SG, Cepko CL, Bhattacharya SS, Mcinnes RR. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific Homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell. 1997;91:543–53.CrossRefGoogle Scholar
  104. 104.
    Tzekov RT, Liu Y, Sohocki MM, Zack DJ, Daiger SP, Heckenlively JR, Birch DG. Autosomal dominant retinal degeneration and bone loss in patients with a 12-bp deletion in the CRX gene. Invest Ophthalmol Vis Sci. 2001;42:1319–27.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Sorsby A, Williams CE. Retinal aplasia as a clinical entity. Br Med J. 1960;1:293.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Deangelis MM, Grimsby JL, Sandberg MA, Berson EL, Dryja TP. Novel mutations in the NRL gene and associated clinical findings in patients with dominant retinitis pigmentosa. Arch Ophthalmol. 2002;120:369–75.CrossRefGoogle Scholar
  107. 107.
    Nishiguchi KM, Friedman JS, Sandberg MA, Swaroop A, Berson EL, Dryja TP. Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function. Proc Natl Acad Sci U S A. 2004;101:17819–24.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Nichols LL 2nd, Alur RP, Boobalan E, Sergeev YV, Caruso RC, Stone EM, Swaroop A, Johnson MA, Brooks BP. Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL. Hum Mutat. 2010;31:E1472–83.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Swaroop A, Wang QL, Wu W, Cook J, Coats C, Xu S, Chen S, Zack DJ, Sieving PA. Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Hum Mol Genet. 1999;8:299–305.CrossRefGoogle Scholar
  110. 110.
    Van Lith-Verhoeven JJ, Cremers FP, Van Den Helm B, Hoyng CB, Deutman AF. Genetic heterogeneity of butterfly-shaped pigment dystrophy of the fovea. Mol Vis. 2003;9:138–43.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Jinda W, Taylor TD, Suzuki Y, Thongnoppakhun W, Limwongse C, Lertrit P, Trinavarat A, Atchaneeyasakul LO. Whole exome sequencing in eight Thai patients with Leber congenital amaurosis reveals mutations in the CTNNA1 and CYP4V2 genes. Invest Ophthalmol Vis Sci. 2017;58:2413–20.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, Hayakawa M, Kanai A, Shy Chen M, Alan Lewis R, Heckenlively J, Weleber RG, Traboulsi EI, Zhang Q, Xiao X, Kaiser-Kupfer M, Sergeev YV, Hejtmancik JF. Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. Am J Hum Genet. 2004;74:817–26.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, Al-Zahrani J, Al-Abdi L, Hashem M, Al-Tarimi S, Sebai MA, Shamia A, Ray-Zack MD, Nassan M, Al-Hassnan ZN, Rahbeeni Z, Waheeb S, Alkharashi A, Abboud E, Al-Hazzaa SAF, Alkuraya FS. Autozygome-guided exome sequencing in retinal dystrophy patients reveals Pathogenetic mutations and novel candidate disease genes. Genome Res. 2013;23:236–47.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, Chatelin S, Souied E, Ghazi I, Leowski C, Bonnemaison M, Le Paslier D, Frezal J, Dufier JL, Pittler S, Munnich A, Kaplan J. Retinal-specific guanylate cyclase gene mutations in Leber’s congenital amaurosis. Nat Genet. 1996;14:461–4.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Kelsell RE, Gregory-Evans K, Payne AM, Perrault I, Kaplan J, Yang RB, Garbers DL, Bird AC, Moore AT, Hunt DM. Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Hum Mol Genet. 1998;7:1179–84.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Dharmaraj S, Silva E, Pina AL, Li YY, Yang JM, Carter RC, El-Hilali H, Traboulsi E, Sundin O, Zhu D, Koenekoop RK, Maumenee IH. Mutational analysis and clinical correlation in Leber congenital amaurosis. Ophthalmic Genet. 2000b;21:135–50.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Hanein S, Perrault I, Gerber S, Tanguy G, Barbet F, Ducroq D, Calvas P, Dollfus H, Hamel C, Lopponen T, Munier F, Santos L, Shalev S, Zafeiriou D, Dufier JL, Munnich A, Rozet JM, Kaplan J. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat. 2004a;23:306–17.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Dharmaraj S, Silva E, Li YY, Loyer M, Koenekoop RK, Maumenee IH. Mutational analysis in one hundred consecutive patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 1999;40:S565.Google Scholar
  119. 119.
    Xu M, Yang L, Wang F, Li H, Wang X, Wang W, Ge Z, Wang K, Zhao L, Li H, Li Y, Sui R, Chen R. Mutations in human IFT140 cause non-syndromic retinal degeneration. Hum Genet. 2015;134:1069–78.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Bowne SJ, Liu Q, Sullivan LS, Zhu J, Spellicy CJ, Rickman CB, Pierce EA, Daiger SP. Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration? Invest Ophthalmol Vis Sci. 2006a;47:3754–65.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Bowne SJ, Sullivan LS, Mortimer SE, Hedstrom L, Zhu J, Spellicy CJ, Gire AI, Hughbanks-Wheaton D, Birch DG, Lewis RA, Heckenlively JR, Daiger SP. Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis Pigmentosa and Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2006b;47:34–42.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Estrada-Cuzcano A, Koenekoop RK, Coppieters F, Kohl S, Lopez I, Collin RW, De Baere EB, Roeleveld D, Marek J, Bernd A, Rohrschneider K, Van Den Born LI, Meire F, Maumenee IH, Jacobson SG, Hoyng CB, Zrenner E, Cremers FP, Den Hollander AI. IQCB1 mutations in patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2011;52:834–9.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O'Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Coucke P, De Paepe A, Reinhardt R, Klages S, Tsuda M, Kawakami I, Kusakabe T, Omran H, Imm A, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005;37:282–8.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Pattnaik BR, Shahi PK, Marino MJ, Liu X, York N, Brar S, Chiang J, Pillers DA, Traboulsi EI. A novel KCNJ13 nonsense mutation and loss of Kir7.1 channel function causes Leber congenital amaurosis (LCA16). Hum Mutat. 2015;36:720–7.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Sergouniotis PI, Davidson AE, Mackay DS, Li Z, Yang X, Plagnol V, Moore AT, Webster AR. Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital Amaurosis. Am J Hum Genet. 2011;89:183–90.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Zhang W, Zhang X, Wang H, Sharma AK, Edwards AO, Hughes BA. Characterization of the R162W Kir7.1 mutation associated with snowflake vitreoretinopathy. Am J Physiol Cell Physiol. 2013;304:C440–9.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Khan AO, Bergmann C, Neuhaus C, Bolz HJ. A distinct Vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations. Ophthalmic Genet. 2015;36:79–84.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Den Hollander AI, Koenekoop RK, Mohamed MD, Arts HH, Boldt K, Towns KV, Sedmak T, Beer M, Nagel-Wolfrum K, Mckibbin M, Dharmaraj S, Lopez I, Ivings L, Williams GA, Springell K, Woods CG, Jafri H, Rashid Y, Strom TM, Van Der Zwaag B, Gosens I, Kersten FF, Van Wijk E, Veltman JA, Zonneveld MN, Van Beersum SE, Maumenee IH, Wolfrum U, Cheetham ME, Ueffing M, Cremers FP, Inglehearn CF, Roepman R. Mutations in LCA5, encoding the ciliary protein Lebercilin, cause Leber congenital amaurosis. Nat Genet. 2007;39:889–95.CrossRefGoogle Scholar
  129. 129.
    Dharmaraj S, Li Y, Robitaille JM, Silva E, Zhu D, Mitchell TN, Maltby LP, Baffoe-Bonnie AB, Maumenee IH. A novel locus for Leber congenital amaurosis maps to chromosome 6q. Am J Hum Genet. 2000a;66:319–26.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Mohamed MD, Topping NC, Jafri H, Raashed Y, Mckibbin MA, Inglehearn CF. Progression of phenotype in Leber’s congenital amaurosis with a mutation at the LCA5 locus. Br J Ophthalmol. 2003b;87:473–5.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Ozgul R, Bozkurt B, Kiratli H, Ogus A. Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA. Eye. 2006;20:817–9.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Chen X, Sheng X, Sun X, Zhang Y, Jiang C, Li H, Ding S, Liu Y, Liu W, Li Z, Zhao C. Next-generation sequencing extends the phenotypic Spectrum for LCA5 mutations: novel LCA5 mutations in cone dystrophy. Sci Rep. 2016;6:24357.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Ramprasad VL, Soumittra N, Nancarrow D, Sen P, Mckibbin M, Williams GA, Arokiasamy T, Lakshmipathy P, Inglehearn CF, Kumaramanickavel G. Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis. Mol Vis. 2008;14:481–6.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Ahmad A, Daud S, Kakar N, Nurnberg G, Nurnberg P, Babar ME, Thoenes M, Kubisch C, Ahmad J, Bolz HJ. Identification of a novel LCA5 mutation in a Pakistani family with Leber congenital amaurosis and cataracts. Mol Vis. 2011;17:1940–5.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Mackay DS, Borman AD, Sui R, Van Den Born LI, Berson EL, Ocaka LA, Davidson AE, Heckenlively JR, Branham K, Ren H, Lopez I, Maria M, Azam M, Henkes A, Blokland E, Andreasson S, De Baere E, Bennett J, Chader GJ, Berger W, Golovleva I, Greenberg J, Den Hollander AI, Klaver CC, Klevering BJ, Lorenz B, Preising MN, Ramesar R, Roberts L, Roepman R, Rohrschneider K, Wissinger B, Qamar R, Webster AR, Cremers FP, Moore AT, Koenekoop RK. Screening of a large cohort of Leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. Hum Mutat. 2013;34:1537–46.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Ruiz A, Winston A, Lim YH, Gilbert BA, Rando RR, Bok D. Molecular and biochemical characterization of lecithin retinol acyltransferase. J Biol Chem. 1999;274:3834–41.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Borman AD, Ocaka LA, Mackay DS, Ripamonti C, Henderson RH, Moradi P, Hall G, Black GC, Robson AG, Holder GE, Webster AR, Fitzke F, Stockman A, Moore AT. Early onset retinal dystrophy due to mutations in LRAT: molecular analysis and detailed phenotypic study. Invest Ophthalmol Vis Sci. 2012;53:3927–38.CrossRefGoogle Scholar
  138. 138.
    Thompson DA, Li Y, Mchenry CL, Carlson TJ, Ding X, Sieving PA, Apfelstedt-Sylla E, Gal A. Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy. Nat Genet. 2001;28:123–4.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Weil D, Blanchard S, Kaplan J, Guilford P, Gibson F, Walsh J, Mburu P, Varela A, Levilliers J, Weston MD, et al. Defective myosin VIIA gene responsible for usher syndrome type 1B. Nature. 1995;374:60–1.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Keen TJ, Mohamed MD, Mckibbin M, Rashid Y, Jafri H, Maumenee IH, Inglehearn CF. Identification of a locus (LCA9) for Leber’s congenital amaurosis on chromosome 1p36. Eur J Hum Genet. 2003;11:420–3.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Mohamed MD, Keen TJ, Mckibbin MA, Raashed Y, Jafri H, Maumenee IH, Inglehearn CF. Identification of LCA9, a new locus for Leber’s congenital amaurosis on chromosome 1p36. Invest Ophthalmol Vis Sci. 2003a;44:U350.Google Scholar
  142. 142.
    Chiang PW, Wang J, Chen Y, Fu Q, Zhong J, Chen Y, Yi X, Wu R, Gan H, Shi Y, Chen Y, Barnett C, Wheaton D, Day M, Sutherland J, Heon E, Weleber RG, Gabriel LA, Cong P, Chuang K, Ye S, Sallum JM, Qi M. Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis. Nat Genet. 2012;44:972–4.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Falk MJ, Zhang Q, Nakamaru-Ogiso E, Kannabiran C, Fonseca-Kelly Z, Chakarova C, Audo I, Mackay DS, Zeitz C, Borman AD, Staniszewska M, Shukla R, Palavalli L, Mohand-Said S, Waseem NH, Jalali S, Perin JC, Place E, Ostrovsky J, Xiao R, Bhattacharya SS, Consugar M, Webster AR, Sahel JA, Moore AT, Berson EL, Liu Q, Gai X, Pierce EA. NMNAT1 mutations cause Leber congenital amaurosis. Nat Genet. 2012;44:1040–5.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y, Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan CV, Mckibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M, Finding Of Rare Disease Genes Canada, C, Poulter JA, Mohamed MD, Jafri H, Rashid Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat Genet. 2012;44:1035–9.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Henderson RH, Williamson KA, Kennedy JS, Webster AR, Holder GE, Robson AG, Fitzpatrick DR, Van Heyningen V, Moore AT. A rare de novo nonsense mutation in OTX2 causes early onset retinal dystrophy and pituitary dysfunction. Mol Vis. 2009;15:2442–7.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Kmoch S, Majewski J, Ramamurthy V, Cao S, Fahiminiya S, Ren H, Macdonald IM, Lopez I, Sun V, Keser V, Khan A, Stranecky V, Hartmannova H, Pristoupilova A, Hodanova K, Piherova L, Kuchar L, Baxova A, Chen R, Barsottini OGP, Pyle A, Griffin H, Splitt M, Sallum J, Tolmie JL, Sampson JR, Chinnery P, Banin E, Sharon D, Dutta S, Grebler R, Helfrich-Foerster C, Pedroso JL, Kretzschmar D, Cayouette M, Koenekoop RK, Care4Rare, C. Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness. Nat Commun. 2015;6:5614.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-Mcfarlane and Laurence-Moon syndromes. J Med Genet. 2015;52:85–94.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Schubert SF, Hoffjan S, Dekomien G. Mutational analysis of the CYP7B1, PNPLA6 and C19orf12 genes in autosomal recessive hereditary spastic paraplegia. Mol Cell Probes. 2016;30:53–5.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Roosing S, Lamers IJC, De Vrieze E, Van Den Born LI, Lambertus S, Arts HH, Peters TA, Hoyng CB, Kremer H, Hetterschijt L, Letteboer SJF, Van Wijk E, Roepman R, Den Hollander AI, Cremers FPM, Grp PBS. Disruption of the basal body protein POC1B results in autosomal-recessive cone-rod dystrophy. Am J Hum Genet. 2014;95:131–42.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Durlu YK, Koroglu C, Tolun A. Novel recessive cone-rod dystrophy caused by POC1B mutation. JAMA Ophthalmol. 2014;132:1185–91.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Beck BB, Phillips JB, Bartram MP, Wegner J, Thoenes M, Pannes A, Sampson J, Heller R, Gobel H, Koerber F, Neugebauer A, Hedergott A, Nurnberg G, Nurnberg P, Thiele H, Altmuller J, Toliat MR, Staubach S, Boycott KM, Valente EM, Janecke AR, Eisenberger T, Bergmann C, Tebbe L, Wang Y, Wu Y, Fry AM, Westerfield M, Wolfrum U, Bolz HJ. Mutation of POC1B in a severe syndromic retinal ciliopathy. Hum Mutat. 2014;35:1153–62.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Khan AO, Al Rashaed S, Neuhaus C, Bergmann C, Bolz HJ. Peripherin mutations cause a distinct form of recessive Leber congenital amaurosis and dominant phenotypes in asymptomatic parents heterozygous for the mutation. Br J Ophthalmol. 2016;100:209–15.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Preising MN, Hausotter-Will N, Solbach MC, Friedburg C, Ruschendorf F, Lorenz B. Mutations in RD3 are associated with an extremely rare and severe form of early onset retinal dystrophy. Invest Ophthalmol Vis Sci. 2012;53:3463–72.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Jacobson SG, Cideciyan AV, Aleman TS, Sumaroka A, Schwartz SB, Windsor EA, Roman AJ, Heon E, Stone EM, Thompson DA. RDH12 and RPE65, visual cycle genes causing Leber congenital amaurosis, differ in disease expression. Invest Ophthalmol Vis Sci. 2007;48:332–8.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Redmond TM, Poliakov E, Yu S, Tsai JY, Lu Z, Gentleman S. Mutation of key residues of RPE65 abolishes its enzymatic role as Isomerohydrolase in the visual cycle. Proc Natl Acad Sci U S A. 2005;102:13658–63.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Gu SM, Thompson DA, Srikumari CR, Lorenz B, Finckh U, Nicoletti A, Murthy KR, Rathmann M, Kumaramanickavel G, Denton MJ, Gal A. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat Genet. 1997;17:194–7.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Joseph B, Srinivasan A, Soumittra N, Vidhya A, Shetty NS, Uthra S, Kumaramanickavel G. RPE65 gene: multiplex PCR and mutation screening in patients from India with retinal degenerative diseases. J Genet. 2002;81:19–23.CrossRefGoogle Scholar
  158. 158.
    Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, Liu SY, Harris E, Redmond TM, Arnaud B, Claustres M. Mutations in RPE65 cause Leber’s congenital amaurosis. Nat Genet. 1997;17:139–41.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP. Mutations in the RPE65 gene in patients with autosomal recessive retinitis Pigmentosa or Leber congenital amaurosis. Proc Natl Acad Sci U S A. 1998;95:3088–93.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Perrault I, Rozet JM, Gerber S, Ducroq D, Ghazi I, Leowski C, Souied E, Dufier JL, Munnich A, Kaplan J. Extensive screening of four disease causing genes and several candidate genes in 130 families affected with Leber congenital amaurosis. Am J Hum Genet. 2000;67:411.Google Scholar
  161. 161.
    Thompson DA, Gyurus P, Fleischer LL, Bingham EL, Mchenry CL, Apfelstedt-Sylla E, Zrenner E, Lorenz B, Richards JE, Jacobson SG, Sieving PA, Gal A. Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest Ophthalmol Vis Sci. 2000;41:4293–9.PubMedGoogle Scholar
  162. 162.
    Yzer S, Van Den Born LI, Schuil J, Kroes HY, Van Genderen MM, Boonstra FN, Van Den Helm B, Brunner HG, Koenekoop RK, Cremers FPM. A Tyr368His RPE65 founder mutation is associated with variable expression and progression of early onset retinal dystrophy in 10 families of a genetically isolated population. J Med Genet. 2003;40:709–13.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Galvin JA, Fishman GA, Stone EM, Koenekoop RK. Evaluation of genotype-phenotype associations in leber congenital amaurosis. Retina. 2005b;25:919–29.CrossRefGoogle Scholar
  164. 164.
    Xu F, Dong Q, Liu L, Li H, Liang X, Jiang R, Sui R, Dong F. Novel RPE65 mutations associated with Leber congenital amaurosis in Chinese patients. Mol Vis. 2012;18:744–50.PubMedPubMedCentralGoogle Scholar
  165. 165.
    Zhao Y, Hong DH, Pawlyk B, Yue G, Adamian M, Grynberg M, Godzik A, Li T. The retinitis Pigmentosa Gtpase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis. Proc Natl Acad Sci U S A. 2003;100:3965–70.CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Meindl A, Dry K, Herrmann K, Manson F, Ciccodicola A, Edgar A, Carvalho MR, Achatz H, Hellebrand H, Lennon A, Migliaccio C, Porter K, Zrenner E, Bird A, Jay M, Lorenz B, Wittwer B, D'Urso M, Meitinger T, Wright A. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis Pigmentosa (RP3). Nat Genet. 1996;13:35–42.CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Dryja TP, Adams SM, Grimsby JL, Mcgee TL, Hong DH, Li T, Andreasson S, Berson EL. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet. 2001;68:1295–8.CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Gerber S, Perrault I, Hanein S, Barbet F, Ducroq D, Ghazi I, Dufier JL, Munnich A, Kaplan J, Rozet JM. Mutations in the retinitis pigmentosa GTPase regulator interacting protein (RPGRIP1) gene are responsible for leber congenital amaurosis. Am J Hum Genet. 2001;69:229.Google Scholar
  169. 169.
    Hameed A, Abid A, Aziz A, Ismail M, Mehdi SQ, Khaliq S. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy. J Med Genet. 2003;40:616–9.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Abouzeid H, Othman IS, Schorderet DF. A novel recessive RPGRIP1 mutation causing Leber congenital amaurosis. Klin Monatsbl Augenheilkd. 2016;233:456–9.CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Janecke AR, Thompson DA, Utermann G, Becker C, Hubner CA, Schmid E, Mchenry CL, Nair AR, Ruschendorf F, Heckenlively J, Wissinger B, Nurnberg P, Gal A. Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy. Nat Genet. 2004;36:850–4.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Perrault I, Hanein S, Gerber S, Barbet F, Ducroq D, Dollfus H, Hamel C, Dufier JL, Munnich A, Kaplan J, Rozet JM. Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis. Am J Hum Genet. 2004;75(4):639–646Google Scholar
  173. 173.
    Haeseleer F, Jang GF, Imanishi Y, Driessen C, Matsumura M, Nelson PS, Palczewski K. Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina. J Biol Chem. 2002;277:45537–46.CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Eblimit A, Nguyen TM, Chen Y, Esteve-Rudd J, Zhong H, Letteboer S, Van Reeuwijk J, Simons DL, Ding Q, Wu KM, Li Y, Van Beersum S, Moayedi Y, Xu H, Pickard P, Wang K, Gan L, Wu SM, Williams DS, Mardon G, Roepman R, Chen R. SPATA7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina. Hum Mol Genet. 2015;24:1584–601.CrossRefGoogle Scholar
  175. 175.
    Stockton DW, Lewis RA, Abboud EB, Al-Rajhi A, Jabak M, Anderson KL, Lupski JR. A novel locus for Leber congenital amaurosis on chromosome 14q24. Hum Genet. 1998;103:328–33.CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Lewis CA, Batlle IR, Batlle KG, Banerjee P, Cideciyan AV, Huang J, Aleman TS, Huang Y, Ott J, Gilliam TC, Knowles JA, Jacobson SG. Tubby-like protein 1 homozygous splice-site mutation causes early-onset severe retinal degeneration. Invest Ophthalmol Vis Sci. 1999;40:2106–14.PubMedGoogle Scholar
  177. 177.
    North MA, Naggert JK, Yan Y, Noben-Trauth K, Nishina PM. Molecular characterization of tub, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. Proc Natl Acad Sci U S A. 1997;94:3128–33.CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Milam AH, Hendrickson AE, Xiao M, Smith JE, Possin DE, John SK, Nishina PM. Localization of tubby-like protein 1 in developing and adult human retinas. Invest Ophthalmol Vis Sci. 2000;41:2352–6.PubMedGoogle Scholar
  179. 179.
    Abbasi AH, Garzozi HJ, Ben-Yosef T. A novel splice-site mutation of TULP1 underlies severe early-onset retinitis Pigmentosa in a consanguineous Israeli Muslim Arab family. Mol Vis. 2008;14:675–82.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Zernant J, Kulm M, Dharmaraj S, Den Hollander AI, Perrault I, Preising MN, Lorenz B, Kaplan J, Cremers FP, Maumenee I, Koenekoop RK, Allikmets R. Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. Invest Ophthalmol Vis Sci. 2005;46:3052–9.CrossRefPubMedGoogle Scholar
  181. 181.
    Felius J, Thompson DA, Khan NW, Bingham EL, Jamison JA, Kemp JA, Sieving PA. Clinical course and visual function in a family with mutations in the RPE65 gene. Arch Ophthalmol. 2002;120:55–61.CrossRefPubMedGoogle Scholar
  182. 182.
    Paunescu K, Wabbels B, Preising MN, Lorenz B. Longitudinal and cross-sectional study of patients with early-onset severe retinal dystrophy associated with RPE65 mutations. Graefes Arch Clin Exp Ophthalmol. 2005;243:417–26.CrossRefPubMedGoogle Scholar
  183. 183.
    Perrault I, Rozet JM, Ghazi I, Leowski C, Bonnemaison M, Gerber S, Ducroq D, Cabot A, Souied E, Dufier JL, Munnich A, Kaplan J. Different functional outcome of RETGC1 and RPE65 gene mutations in Leber congenital amaurosis. Am J Hum Genet. 1999b;64:1225–8.CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Coussa RG, Lopez Solache I, Koenekoop RK. Leber congenital amaurosis, from darkness to light: an ode to Irene Maumenee. Ophthalmic Genet. 2017;38:7–15.CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Fulton AB, Hansen RM, Luisa Mayer D. Vision in leber congenital amaurosis. Arch Ophthalmol. 1996;114:698–703.CrossRefPubMedGoogle Scholar
  186. 186.
    Koenekoop RK, Loyer M, Dembinska O, Beneish R. Visual improvement in Leber congenital amaurosis and the CRX genotype. Ophthalmic Genet. 2002b;23:49–59.CrossRefPubMedGoogle Scholar
  187. 187.
    Lorenz B, Gyurus P, Preising M, Bremser D, Gu S, Andrassi M, Gerth C, Gal A. Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Invest Ophthalmol Vis Sci. 2000;41:2735–42.PubMedGoogle Scholar
  188. 188.
    Brecelj J, Stirn-Kranjc B. ERG and VEP follow-up study in children with Leber’s congenital amaurosis. Eye. 1999;13:47–54.CrossRefPubMedGoogle Scholar
  189. 189.
    Heher KL, Traboulsi EI, Maumenee IH. Visual-acuity and retinal appearance in leber congenital amaurosis – findings in 20 patients with long-term follow-up. Invest Ophthalmol Vis Sci. 1991;32:911.Google Scholar
  190. 190.
    Perrault I, Rozet JM, Gerber S, Ghazi I, Leowski C, Ducroq D, Souied E, Dufier JL, Munnich A, Kaplan J. Leber congenital amaurosis. Mol Genet Metab. 1999a;68:200–8.CrossRefPubMedGoogle Scholar
  191. 191.
    Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol. 2017;101:1147–54.CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Yzer S, Leroy BP, De Baere E, De Ravel TJ, Zonneveld MN, Voesenek K, Kellner U, Ciriano JP, De Faber JT, Rohrschneider K, Roepman R, Den Hollander AI, Cruysberg JR, Meire F, Casteels I, Van Moll-Ramirez NG, Allikmets R, Van Den Born LI, Cremers FP. Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2006;47:1167–76.CrossRefPubMedGoogle Scholar
  193. 193.
    Den Hollander AI, Davis J, Van Der Velde-Visser SD, Zonneveld MN, Pierrottet CO, Koenekoop RK, Kellner U, Van Den Born LI, Heckenlively JR, Hoyng CB, Handford PA, Roepman R, Cremers FP. CRB1 mutation Spectrum in inherited retinal dystrophies. Hum Mutat. 2004;24:355–69.CrossRefGoogle Scholar
  194. 194.
    Suthers GK, Davies KE. Phenotypic heterogeneity and the single gene. Am J Hum Genet. 1992;50:887–91.PubMedPubMedCentralGoogle Scholar
  195. 195.
    Garg A, Lee W, Sengillo JD, Allikmets R, Garg K, Tsang SH. Peripapillary sparing In RDH12-associated leber congenital amaurosis. Ophthalmic Genetics. 2017;38(6):575–9.CrossRefPubMedGoogle Scholar
  196. 196.
    Scholl HP, Chong NH, Robson AG, Holder GE, Moore AT, Bird AC. Fundus autofluorescence in patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2004;45:2747–52.CrossRefPubMedGoogle Scholar
  197. 197.
    Hanein S, Perrault I, Olsen P, Lopponen T, Hietala M, Gerber S, Jeanpierre M, Barbet F, Ducroq D, Hakiki S, Munnich A, Rozet JM, Kaplan J. Evidence of a founder effect for the RETGC1 (GUCY2D) 2943DelG mutation in Leber congenital amaurosis pedigrees of Finnish origin. Hum Mutat. 2002;20:322–3.CrossRefPubMedGoogle Scholar
  198. 198.
    Banin E, Bandah-Rozenfeld D, Obolensky A, Cideciyan AV, Aleman TS, Marks-Ohana D, Sela M, Boye S, Sumaroka A, Roman AJ, Schwartz SB, Hauswirth WW, Jacobson SG, Hemo I, Sharon D. Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel. Hum Gene Ther. 2010;21:1749–57.CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Damji KF, Sohocki MM, Khan R, Gupta SK, Rahim M, Loyer M, Hussein N, Karim N, Ladak SS, Jamal A, Bulman D, Koenekoop RK. Leber’s congenital amaurosis with anterior keratoconus in Pakistani families is caused by the TRP278X mutation in the AIPL1 gene on 17p. Can J Ophthalmol. 2001;36:252–9.CrossRefPubMedGoogle Scholar
  200. 200.
    Hanein S, Perrault I, Gerber S, Tanguy G, Rozet JM, Kaplan J. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition and phenotype-genotype correlations as a strategy for molecular diagnosis. Invest Ophthalmol Vis Sci. 2004b;45:U509.Google Scholar
  201. 201.
    De Pool ME, El-Hileli H, Maumenee IH, Wilkinson CP, Lewis RA. The Ateliotic macula: a newly recognized developmental anomaly. Trans Am Ophthalmol Soc. 2001;99:89–94.PubMedPubMedCentralGoogle Scholar
  202. 202.
    Silva E, Yang JM, Li Y, Dharmaraj S, Sundin OH, Maumenee IH. A CRX null mutation is associated with both Leber congenital amaurosis and a normal ocular phenotype. Invest Ophthalmol Vis Sci. 2000;41:2076–9.PubMedGoogle Scholar
  203. 203.
    Koenekoop RK, Fishman GA, Iannaccone A, Ezzeldin H, Ciccarelli ML, Baldi A, Sunness JS, Lotery AJ, Jablonski MM, Pittler SJ, Maumenee I. Electroretinographic abnormalities in parents of patients with Leber congenital amaurosis who have heterozygous GUCY2D mutations. Arch Ophthalmol. 2002a;120:1325–30.CrossRefPubMedGoogle Scholar
  204. 204.
    Seong MW, Kim SY, Yu YS, Hwang JM, Kim JY, Park SS. Molecular characterization of Leber congenital amaurosis in Koreans. Mol Vis. 2008;14:1429–36.PubMedPubMedCentralGoogle Scholar
  205. 205.
    Leveillard T, Mohand-Said S, Lorentz O, Hicks D, Fintz AC, Clerin E, Simonutti M, Forster V, Cavusoglu N, Chalmel F, Dolle P, Poch O, Lambrou G, Sahel JA. Identification and characterization of rod-derived cone viability factor. Nat Genet. 2004;36:755–9.CrossRefPubMedGoogle Scholar
  206. 206.
    Sahel JA, Mohand-Said S, Leveillard T, Hicks D, Picaud S, Dreyfus H. Rod-cone interdependence: implications for therapy of photoreceptor cell diseases. Prog Brain Res. 2001;131:649–61.CrossRefPubMedGoogle Scholar
  207. 207.
    Dejneka NS, Rex TS, Bennett J. Gene therapy and animal models for retinal disease. Dev Ophthalmol. 2003;37:188–98.CrossRefPubMedGoogle Scholar
  208. 208.
    Streilein JW, Ma N, Wenkel H, Ng TF, Zamiri P. Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vis Res. 2002;42:487–95.CrossRefPubMedGoogle Scholar
  209. 209.
    Ali RR, Reichel MB, Thrasher AJ, Levinsky RJ, Kinnon C, Kanuga N, Hunt DM, Bhattacharya SS. Gene transfer into the mouse retina mediated by an adeno-associated viral vector. Hum Mol Genet. 1996;5:591–4.CrossRefPubMedGoogle Scholar
  210. 210.
    Bennett J, Maguire AM, Cideciyan AV, Schnell M, Glover E, Anand V, Aleman TS, Chirmule N, Gupta AR, Huang Y, Gao GP, Nyberg WC, Tazelaar J, Hughes J, Wilson JM, Jacobson SG. Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina. Proc Natl Acad Sci U S A. 1999;96:9920–5.CrossRefPubMedPubMedCentralGoogle Scholar
  211. 211.
    Dejneka NS, Bennett J. Gene therapy and retinitis Pigmentosa: advances and future challenges. BioEssays. 2001;23:662–8.CrossRefGoogle Scholar
  212. 212.
    Narfstrom K, Bragadottir R, Redmond TM, Rakoczy PE, Van Veen T, Bruun A. Functional and structural evaluation after AAV.RPE65 gene transfer in the canine model of Leber’s congenital amaurosis. Adv Exp Med Biol. 2003;533:423–30.CrossRefGoogle Scholar
  213. 213.
    Dejneka NS, Surace EM, Aleman TS, Cideciyan AV, Lyubarsky A, Savchenko A, Redmond TM, Tang W, Wei Z, Rex TS, Glover E, Maguire AM, Pugh EN Jr, Jacobson SG, Bennett J. In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther. 2004;9:182–8.CrossRefGoogle Scholar
  214. 214.
    Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28:92–5.PubMedGoogle Scholar
  215. 215.
    Bainbridge JWB, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358:2231–9.CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19:979–90.CrossRefPubMedPubMedCentralGoogle Scholar
  217. 217.
    Jacobson SG, Cideciyan AV, Ratnakaram R, Heon E, Schwartz SB, Roman AJ, Peden MC, Aleman TS, Boye SL, Sumaroka A, Conlon TJ, Calcedo R, Pang JJ, Erger KE, Olivares MB, Mullins CL, Swider M, Kaushal S, Feuer WJ, Iannaccone A, Fishman GA, Stone EM, Byrne BJ, Hauswirth WW. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130:9–24.CrossRefGoogle Scholar
  218. 218.
    Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, Mingozzi F, Bennicelli JL, Ying GS, Rossi S, Fulton A, Marshall KA, Banfi S, Chung DC, Morgan JIW, Hauck B, Zelenaia O, Zhu XS, Raffini L, Coppieters F, De Baere E, Shindler KS, Volpe NJ, Surace EM, Acerra C, Lyubarsky A, Redmond TM, Stone E, Sun JW, Mcdonnell JW, Leroy BP, Simonelli F, Bennett J. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374:1597–605.CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, Mcdonnell JW, High KA, Bennett J, Auricchio A. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010;18:643–50.CrossRefGoogle Scholar
  220. 220.
    Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, Roman AJ, Olivares MB, Schwartz SB, Komáromy AM, Hauswirth WW, Aguirre GD. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U. S. A. 2013;110:E517–25.CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Jacobson SG, Cideciyan AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, Hauswirth WW. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015b;372:1920–6.CrossRefPubMedPubMedCentralGoogle Scholar
  222. 222.
    Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, Banfi S, Surace EM, Sun J, Acerra C, Wright JF, Wellman J, High KA, Auricchio A, Bennett J, Simonelli F. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital amaurosis type 2. Ophthalmology. 2013;120:1283–91.CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Jacobson SG, Cideciyan AV, Aguirre GD, Roman AJ, Sumaroka A, Hauswirth WW, Palczewski K. Improvement in vision: a new goal for treatment of hereditary retinal degenerations. Expert Opin Orphan Drugs. 2015a;3:563–75.CrossRefPubMedPubMedCentralGoogle Scholar
  224. 224.
    Collin RW, Den Hollander AI, Van Der Velde-Visser SD, Bennicelli J, Bennett J, Cremers FP. Antisense Oligonucleotide (AON)-based therapy for Leber congenital amaurosis caused by a frequent mutation in CEP290. Mol Ther Nucleic Acids. 2012;1:E14.CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Garanto A, Chung DC, Duijkers L, Corral-Serrano JC, Messchaert M, Xiao R, Bennett J, Vandenberghe LH, Collin RW. In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery. Hum Mol Genet. 2016;25(12):2552–63.PubMedPubMedCentralGoogle Scholar
  226. 226.
    Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, Mcdonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358:2240–8.CrossRefPubMedPubMedCentralGoogle Scholar
  227. 227.
    Pawlyk BS, Bulgakov OV, Liu X, Xu X, Adamian M, Sun X, Khani SC, Berson EL, Sandberg MA, Li T. Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis. Hum Gene Ther. 2010;21:993–1004.CrossRefPubMedPubMedCentralGoogle Scholar
  228. 228.
    Kauper K, Mcgovern C, Sherman S, Heatherton P, Rapoza R, Stabila P, Dean B, Lee A, Borges S, Bouchard B, Tao W. Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases. Invest Ophthalmol Vis Sci. 2012;53:7484–91.CrossRefGoogle Scholar
  229. 229.
    Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ, Fullmer KR, Bush RA. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci U S A. 2006;103:3896–901.CrossRefPubMedPubMedCentralGoogle Scholar
  230. 230.
    Cayouette M, Gravel C. Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse. Hum Gene Ther. 1997;8:423–30.CrossRefGoogle Scholar
  231. 231.
    Koenekoop RK, Sui R, Sallum J, Van Den Born LI, Ajlan R, Khan A, Den Hollander AI, Cremers FP, Mendola JD, Bittner AK, Dagnelie G, Schuchard RA, Saperstein DA. Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial. Lancet. 2014;384:1513–20.CrossRefPubMedPubMedCentralGoogle Scholar
  232. 232.
    Fintz AC, Audo I, Hicks D, Mohand-Said S, Leveillard T, Sahel J. Partial characterization of retina-derived cone neuroprotection in two culture models of photoreceptor degeneration. Invest Ophthalmol Vis Sci. 2003;44:818–25.CrossRefPubMedPubMedCentralGoogle Scholar
  233. 233.
    Schwartz SD, Tan G, Hosseini H, Nagiel A. Subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium for the treatment of macular degeneration: an assessment at 4 years. Invest Ophthalmol Vis Sci. 2016;57:Orsfc1-9.CrossRefPubMedPubMedCentralGoogle Scholar
  234. 234.
    Dalkara D, Goureau O, Marazova K, Sahel JA. Let there be light: gene and cell therapy for blindness. Hum Gene Ther. 2016;27:134–47.CrossRefPubMedPubMedCentralGoogle Scholar
  235. 235.
    Burnight ER, Wiley LA, Drack AV, Braun TA, Anfinson KR, Kaalberg EE, Halder JA, Affatigato LM, Mullins RF, Stone EM, Tucker BA. CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype. Gene Ther. 2014;21:662–72.CrossRefPubMedPubMedCentralGoogle Scholar
  236. 236.
    Margalit E, Maia M, Weiland JD, Greenberg RJ, Fujii GY, Torres G, Piyathaisere DV, O'Hearn TM, Liu W, Lazzi G, Dagnelie G, Scribner DA, De Juan E Jr, Humayun MS. Retinal prosthesis for the blind. Surv Ophthalmol. 2002;47:335–56.CrossRefPubMedPubMedCentralGoogle Scholar
  237. 237.
    Weiland JD, Humayun MS. Retinal prosthesis. IEEE Trans Biomed Eng. 2014;61:1412–24.CrossRefPubMedPubMedCentralGoogle Scholar
  238. 238.
    Luo YH, Da Cruz L. The Argus((R)) II retinal prosthesis system. Prog Retin Eye Res. 2016;50:89–107.CrossRefPubMedPubMedCentralGoogle Scholar
  239. 239.
    Luo YH, Fukushige E, Da Cruz L. The potential of the second sight system bionic eye implant for partial sight restoration. Expert Rev Med Devices. 2016;13:673–81.CrossRefPubMedPubMedCentralGoogle Scholar
  240. 240.
    Sadato N, Okada T, Kubota K, Yonekura Y. Tactile discrimination activates the visual cortex of the recently blind naive to Braille: a functional magnetic resonance imaging study in humans. Neurosci Lett. 2004;359:49–52.CrossRefPubMedPubMedCentralGoogle Scholar
  241. 241.
    Nakauchi K, Fujikado T, Kanda H, Morimoto T, Choi JS, Ikuno Y, Sakaguchi H, Kamei M, Ohji M, Yagi T, Nishimura S, Sawai H, Fukuda Y, Tano Y. Transretinal electrical stimulation by an intrascleral multichannel electrode Array in rabbit eyes. Graefes Arch Clin Exp Ophthalmol. 2005;243:169–74.CrossRefPubMedPubMedCentralGoogle Scholar
  242. 242.
    Zrenner E. The subretinal implant: can microphotodiode arrays replace degenerated retinal photoreceptors to restore vision? Ophthalmologica. 2002;216(Suppl 1):8–20. Discussion 52-3CrossRefPubMedPubMedCentralGoogle Scholar
  243. 243.
    Viola MV, Patrinos AA. A Neuroprosthesis for restoring sight. Acta Neurochir Suppl. 2007;97:481–6.CrossRefPubMedPubMedCentralGoogle Scholar
  244. 244.
    Matsuo T, Uchida T, Nitta M, Yamashita K, Takei S, Ido D, Tanaka M, Oguchi M, Furukawa T. Subretinal implantation of Okayama University-type retinal prosthesis (OUReP(TM)) in canine eyes by vitrectomy. J Vet Med Sci. 2017;79:1939–46.CrossRefPubMedPubMedCentralGoogle Scholar
  245. 245.
    Dobelle WH. Artificial vision for the blind by connecting a television camera to the visual cortex. ASAIO J. 2000;46:3–9.CrossRefPubMedPubMedCentralGoogle Scholar
  246. 246.
    Macaluso E, Driver J. Spatial attention and Crossmodal interactions between vision and touch. Neuropsychologia. 2001;39:1304–16.CrossRefPubMedPubMedCentralGoogle Scholar
  247. 247.
    Busskamp V, Roska B. Optogenetic approaches to restoring visual function in retinitis pigmentosa. Curr Opin Neurobiol. 2011;21:942–6.CrossRefPubMedPubMedCentralGoogle Scholar
  248. 248.
    Jacobson SG, Sumaroka A, Luo X, Cideciyan AV. Retinal optogenetic therapies: clinical criteria for candidacy. Clin Genet. 2013;84:175–82.CrossRefPubMedPubMedCentralGoogle Scholar
  249. 249.
    Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA. Clan genomics and the complex architecture of human disease. Cell. 2011;147:32–43.CrossRefPubMedPubMedCentralGoogle Scholar

Online Resources

  1. Exome Variant ServerGoogle Scholar
  2. Human Mutation databaseGoogle Scholar
  3. Exome Aggregation ConsortiumGoogle Scholar
  4. ClinVar Databases.Google Scholar
  5. Leiden online variation databaseGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Sharola Dharmaraj
    • 1
  • Anshuman Verma
    • 2
  • P. Sundaresan
    • 2
  • Chitra Kannabiran
    • 3
  1. 1.Moorfields Eye HospitalLondonUK
  2. 2.Aravind Medical Research Foundation, Aravind Eye HospitalMaduraiIndia
  3. 3.LV Prasad Eye InstituteHyderabadIndia

Personalised recommendations