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Whole exome sequencing analysis identifies novel Stargardt disease-related gene mutations in Chinese Stargardt disease and retinitis pigmentosa patients



To delineate the disease-causing mutations of the Stargardt disease-related genes in Chinese patients diagnosed with Stargardt disease or retinitis pigmentosa (RP) by whole exome sequencing analysis.


A total of 123 sporadic RP or Stargardt disease patients and 2 Stargardt disease families were recruited. All sporadic patients and the probands of the families were subjected to whole exome sequencing analysis. The candidate mutations were verified by direct sequencing based on the cosegregation pattern and in 200 control subjects and by the bioinformatics analyses.


A total of three reported ABCA4 mutations were identified in the probands of the two Stargardt disease families. The probands and the affected family members with either homozygous or compound heterozygous mutations showed typical Stargardt disease features, which was absent in their unaffected family members. The cosegregation pattern confirmed the mode of recessive inheritance. Moreover, two sporadic Stargardt disease patients were identified to carry two novel ABCA4 and one PROM1 mutations. In addition, 13 novel variants were found in 119 sporadic RP patients in 7 Stargardt disease-related genes, and 8 novel missense variants were conserved across different species and predicted to be damaging to the protein. All 15 novel variants were absent in our 200 control subjects.


This study revealed 22.4% study subjects carrying Stargardt disease-related gene mutations with total 15 novel variants in seven Stargardt disease-related genes, assuring that targeted next-generation sequencing analysis is a high throughput strategy to facilitate the clinical diagnosis from suspicious patients and recommended as a routine examination for inherited retinal dystrophies.

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Fig. 1: Pedigrees and clinical characteristics of the two recruited Chinese Stargardt disease families.
Fig. 2: Sanger sequencing confirmation of the identified Stargardt-related gene variants from the whole exome sequencing analysis in patients with Stargardt disease or retinitis pigmentosa.
Fig. 3: Multiple sequence alignment of Stargardt-related gene protein across different species.


  1. Spiteri Cornish K, Ho J, Downes S, Scott NW, Bainbridge J, Lois N. The epidemiology of Stargardt disease in the United Kingdom. Ophthalmol Retin. 2017;1:508–13.

    Article  Google Scholar 

  2. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, et al. Clinical and molecular characteristics of childhood-onset Stargardt disease. Ophthalmology. 2015;122:326–34.

    Article  Google Scholar 

  3. Rotenstreich Y, Fishman GA, Anderson RJ. Visual acuity loss and clinical observations in a large series of patients with Stargardt disease. Ophthalmology. 2003;110:1151–8.

    Article  Google Scholar 

  4. Westeneng-van Haaften SC, Boon CJ, Cremers FP, Hoefsloot LH, den Hollander AI, Hoyng CB. Clinical and genetic characteristics of late-onset Stargardt’s disease. Ophthalmology. 2012;119:1199–210.

    Article  Google Scholar 

  5. Lu LJ, Liu J, Adelman RA. Novel therapeutics for Stargardt disease. Graefes Arch Clin Exp Ophthalmol. 2017;255:1057–62.

    Article  CAS  Google Scholar 

  6. Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15:236–46.

    Article  CAS  Google Scholar 

  7. Corton M, Nishiguchi KM, Avila-Fernandez A, Nikopoulos K, Riveiro-Alvarez R, Tatu SD, et al. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. PLoS ONE. 2013;8:e65574.

    Article  CAS  Google Scholar 

  8. Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, et al. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet. 2001;27:89–93.

    Article  CAS  Google Scholar 

  9. Maw MA, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ, et al. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet. 2000;9:27–34.

    Article  CAS  Google Scholar 

  10. Boon CJ, van Schooneveld MJ, den Hollander AI, van Lith-Verhoeven JJ, Zonneveld-Vrieling MN, Theelen T, et al. Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br J Ophthalmol. 2007;91:1504–11.

    Article  Google Scholar 

  11. Riveiro-Alvarez R, Vallespin E, Wilke R, Garcia-Sandoval B, Cantalapiedra D, Aguirre-Lamban J, et al. Molecular analysis of ABCA4 and CRB1 genes in a Spanish family segregating both Stargardt disease and autosomal recessive retinitis pigmentosa. Mol Vis. 2008;14:262–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Piri N, Gao YQ, Danciger M, Mendoza E, Fishman GA, Farber DB. A substitution of G to C in the cone cGMP-phosphodiesterase gamma subunit gene found in a distinctive form of cone dystrophy. Ophthalmology. 2005;112:159–66.

    Article  Google Scholar 

  13. Zolnikova IV, Strelnikov VV, Skvortsova NA, Tanas AS, Barh D, Rogatina EV, et al. Stargardt disease-associated mutation spectrum of a Russian Federation cohort. Eur J Med Genet. 2017;60:140–7.

    Article  Google Scholar 

  14. Xin W, Xiao X, Li S, Jia X, Guo X, Zhang Q. Identification of genetic defects in 33 probands with Stargardt disease by WES-based bioinformatics gene panel analysis. PLoS ONE. 2015;10:e0132635.

    Article  Google Scholar 

  15. Jiang F, Pan Z, Xu K, Tian L, Xie Y, Zhang X, et al. Screening of ABCA4 gene in a Chinese cohort with Stargardt disease or cone-rod dystrophy with a report on 85 novel mutations. Investig Ophthalmol Vis Sci. 2016;57:145–52.

    Article  CAS  Google Scholar 

  16. Imani S, Cheng J, Shasaltaneh MD, Wei C, Yang L, Fu S, et al. Genetic identification and molecular modeling characterization reveal a novel PROM1 mutation in Stargardt4-like macular dystrophy. Oncotarget. 2018;9:122–41.

    Article  Google Scholar 

  17. Lai Z, Zhang XN, Zhou W, Yu R, Le YP. Evaluation of the ELOVL4 gene in a Chinese family with autosomal dominant STGD3-like macular dystrophy. J Cell Mol Med. 2005;9:961–5.

    Article  CAS  Google Scholar 

  18. Yi J, Li S, Jia X, Xiao X, Wang P, Guo X, et al. Evaluation of the ELOVL4, PRPH2 and ABCA4 genes in patients with Stargardt macular degeneration. Mol Med Rep. 2012;6:1045–9.

    Article  CAS  Google Scholar 

  19. Cremers FPM, Lee W, Collin RWJ, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res. 2020;79:100861.

  20. Ng TK, Tang W, Cao Y, Chen S, Zheng Y, Xiao X, et al. Whole exome sequencing identifies novel USH2A mutations and confirms Usher syndrome 2 diagnosis in Chinese retinitis pigmentosa patients. Sci Rep. 2019;9:5628.

    Article  Google Scholar 

  21. Ran X, Cai WJ, Huang XF, Liu Q, Lu F, Qu J, et al. ‘RetinoGenetics’: a comprehensive mutation database for genes related to inherited retinal degeneration. Database. 2014;2014:bau047.

  22. Rosenberg T, Klie F, Garred P, Schwartz M. N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis. 2007;13:1962–9.

    CAS  PubMed  Google Scholar 

  23. Sisodiya SM, Thompson PJ, Need A, Harris SE, Weale ME, Wilkie SE, et al. Genetic enhancement of cognition in a kindred with cone-rod dystrophy due to RIMS1 mutation. J Med Genet. 2007;44:373–80.

    Article  CAS  Google Scholar 

  24. Albarry MA, Hashmi JA, Alreheli AQ, Albalawi AM, Khan B, Ramzan K, et al. Novel homozygous loss-of-function mutations in RP1 and RP1L1 genes in retinitis pigmentosa patients. Ophthalmic Genet. 2019;40:507–13.

    Article  CAS  Google Scholar 

  25. Khan AO, Bolz HJ. Phenotypic observations in “hypotrichosis with juvenile macular dystrophy” (recessive CDH3 mutations). Ophthalmic Genet. 2016;37:301–6.

    Article  CAS  Google Scholar 

  26. Cehajic-Kapetanovic J, McClements ME, Whitfield J, Shanks M, Clouston P, MacLaren RE. Association of a novel intronic variant in RPGR with hypomorphic phenotype of X-linked retinitis pigmentosa. JAMA Ophthalmol. 2020;138:1151–8.

  27. Liu S, Xie L, Yue J, Ma T, Peng C, Qiu B, et al. Whole-exome sequencing identifies a novel homozygous frameshift mutation in the PROM1 gene as a causative mutation in two patients with sporadic retinitis pigmentosa. Int J Mol Med. 2016;37:1528–34.

    Article  CAS  Google Scholar 

  28. Qi YH, Gao FJ, Hu FY, Zhang SH, Chen JY, Huang WJ, et al. Next-generation sequencing-aided rapid molecular diagnosis of occult macular dystrophy in a Chinese family. Front Genet. 2017;8:107.

    Article  Google Scholar 

  29. Molday RS. Insights into the molecular properties of ABCA4 and its role in the visual cycle and Stargardt disease. Prog Mol Biol Transl Sci. 2015;134:415–31.

    Article  Google Scholar 

  30. Quazi F, Molday RS. Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants. J Biol Chem. 2013;288:34414–26.

    Article  CAS  Google Scholar 

  31. Zhao J, Liao Y, Chen J, Dong X, Gao Z, Zhang H, et al. Aberrant buildup of all-trans-retinal dimer, a nonpyridinium bisretinoid lipofuscin fluorophore, contributes to the degeneration of the retinal pigment epithelium. Investig Ophthalmol Vis Sci. 2017;58:1063–75.

    Article  Google Scholar 

  32. Weigmann A, Corbeil D, Hellwig A, Huttner WB. Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci USA. 1997;94:12425–30.

    Article  CAS  Google Scholar 

  33. Dellett M, Sasai N, Nishide K, Becker S, Papadaki V, Limb GA, et al. Genetic background and light-dependent progression of photoreceptor cell degeneration in prominin-1 knockout mice. Investig Ophthalmol Vis Sci. 2014;56:164–76.

    Article  Google Scholar 

  34. Lu Z, Hu X, Reilly J, Jia D, Liu F, Yu S, et al. Deletion of the transmembrane protein Prom1b in zebrafish disrupts outer-segment morphogenesis and causes photoreceptor degeneration. J Biol Chem. 2019;294:13953–63.

    Article  CAS  Google Scholar 

  35. Noel NCL, MacDonald IM. RP1L1 and inherited photoreceptor disease: a review. Surv Ophthalmol. 2020;65:725–39.

    Article  Google Scholar 

  36. Ahn SJ, Cho SI, Ahn J, Park SS, Park KH, Woo SJ. Clinical and genetic characteristics of Korean occult macular dystrophy patients. Investig Ophthalmol Vis Sci. 2013;54:4856–63.

    Article  Google Scholar 

  37. Strafella C, Caputo V, Pagliaroli G, Iozzo N, Campoli G, Carboni S, et al. NGS analysis for molecular diagnosis of retinitis pigmentosa (RP): detection of a novel variant in PRPH2 gene. Genes. 2019;10:792.

  38. Khan KN, Robson A, Mahroo OAR, Arno G, Inglehearn CF, Armengol M, et al. A clinical and molecular characterisation of CRB1-associated maculopathy. Eur J Hum Genet. 2018;26:687–94.

    Article  CAS  Google Scholar 

  39. Guo X, Li J, Wang Q, Shu Y, Wang J, Chen L, et al. Identification of CRB1 mutations in two Chinese consanguineous families exhibiting autosomal recessive retinitis pigmentosa. Mol Med Rep. 2019;20:2922–8.

    CAS  PubMed  Google Scholar 

  40. Koyanagi Y, Ueno S, Ito Y, Kominami T, Komori S, Akiyama M, et al. Relationship between macular curvature and common causative genes of retinitis pigmentosa in Japanese patients. Investig Ophthalmol Vis Sci. 2020;61:6.

    Article  CAS  Google Scholar 

  41. Birtel J, Eisenberger T, Gliem M, Muller PL, Herrmann P, Betz C, et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018;8:4824.

    Article  Google Scholar 

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The authors would like to express their deepest gratitude to all the participants in this study.


This work was supported by the Special Fund for the Innovative Science and Technology Strategy of Guangdong Province (project code: 180918154960752 to TKN), an internal grant from the Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong (project code: 20-020 to TKN), the National Nature Science Foundation of China (30901646 and 81170853 to HC), YangFan Program and TeZhi Program of Guangdong Province (to HC), and Grant for Key Disciplinary Project of Clinical Medicine under the Guangdong High-level University Development Program, China.

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TKN and HC: conception and design and financial support. YZ and HC: provision of study materials. YC, X-LY, SC, YX, and S-LC: collection and/or assembly of data. TKN, YC, and X-LY: data analysis and interpretation. TKN and X-LY: manuscript writing. TKN and HC: final approval of manuscript.

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Correspondence to Haoyu Chen.

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Ng, T.K., Cao, Y., Yuan, XL. et al. Whole exome sequencing analysis identifies novel Stargardt disease-related gene mutations in Chinese Stargardt disease and retinitis pigmentosa patients. Eye 36, 749–759 (2022).

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