Identification of Two Novel Mutations in ABCA4 Gene in a Patient With Stargardt Disease


Herein we investigated mutations in the ABCA4 gene in an Iranian patient with Stargardt disease using whole exome sequencing (WES). We evaluated genetic alterations in a 13-year-old Iranian girl with Stargardt disease and her family using WES. The target sequences for the proband and her parents were then amplified through polymerase chain reaction (PCR) and the obtained products were screened for mutations in ABCA4 gene by Sanger chain terminating dideoxy nucleotide sequencing. Two novel potentially pathogenic mutations in compound heterozygous state (c.2713del p.E905Rfs*27 and c.5172G>A p.W1724X) were identified in ABCA4 gene which may contribute to the proband’s Stargardt disease phenotype. In general, the WES successfully identified novel causal mutations in ABCA4 gene which may be used for genetic counseling, prenatal diagnosis (PND), and preimplantation genetic diagnosis (PGD) of Stargardt disease.


1. Lu LJ, Liu J, Adelman RA. Novel therapeutics for Stargardt disease. Graefe's Archive for Clinical and Experimental Ophthalmology. 2017;255(6):1057-62.
2. Molday RS. Insights into the Molecular Properties of ABCA4 and Its Role in the Visual Cycle and Stargardt Disease. Progress in Molecular Biology and Translational Science. 2015;134:415-431.
3. Zolnikova IV, Strelnikov VV, Skvortsova NA, Tanas AS, Barh D, Rogatina EV, Egorova IV, Levina DV, Demenkova ON, Prikaziuk EG, Ivanova ME. Stargardt disease-associated mutation spectrum of a Russian Federation cohort. European journal of medical genetics. 2017;60(2):140-7.
4. Zhang J, Qi A, Wang X, Pan H, Mo H, Huang J, Li H, Chen Z, Wei M, Wang B. Novel compound heterozygous mutations in ABCA4 in a Chinese pedigree with Stargardt disease. Molecular Vision. 2016;22:1514.
5. Battu R, Verma A, Hariharan R, Krishna S, Kiran R, Jacob J, Ganapathy A, Ramprasad VL, Kumaramanickavel G, Jeyabalan N, Ghosh A. Identification of novel mutations in ABCA4 gene: clinical and genetic analysis of Indian patients with Stargardt disease. BioMed research international. 2015;2015:940864.
6. Lin B, Cai XB, Zheng ZL, Huang XF, Liu XL, Qu J, Jin ZB. Clinical and genetic analyses reveal novel pathogenic ABCA4 mutations in Stargardt disease families. Scientific reports. 2016;6:35414.
7. Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, Kakuk LE. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nature genetics. 2001;27(1):89-93.
8. Boon CJ, van Schooneveld MJ, den Hollander AI, van Lith-Verhoeven JJ, Zonneveld-Vrieling MN, Theelen T, Cremers FP, Hoyng CB, Klevering BJ. Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. British journal of ophthalmology. 200;91(11):1504-11.
9. Tsybovsky Y, Palczewski K. Expression, purification and structural properties of ABC transporter ABCA4 and its individual domains. Protein expression and purification. 2014;97:50-60.
10. Molday RS, Zhong M, Quazi F. The role of the photoreceptor ABC transporter ABCA4 in lipid transport and Stargardt macular degeneration. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2009;1791(7):573-83.
11. Molday RS, Zhang K. Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Progress in lipid research. 2010;49(4):476-92.
12. Xiang Q, Cao Y, Xu H, Guo Y, Yang Z, Xu L, Yuan L, Deng H. Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease. Bioscience reports. 2019;39(1):1-8.
13. Huang X, Yuan L, Xu H, Zheng W, Cao Y, Yi J, Guo Y, Yang Z, Li Y, Deng H. Identification of a novel mutation in the ABCA4 gene in a Chinese family with retinitis pigmentosa using exome sequencing. Bioscience reports. 2018;38(2):1-6.
14. Cornelis SS, Bax NM, Zernant J, Allikmets R, Fritsche LG, den Dunnen JT, Ajmal M, Hoyng CB, Cremers FP. In silico functional meta‐analysis of 5,962 ABCA4 variants in 3,928 retinal dystrophy cases. Human mutation. 2017;38(4):400-8.
15. Schulz HL, Grassmann F, Kellner U, Spital G, Rüther K, Jägle H, Hufendiek K, Huchzermeyer C, Baier MJ, Weber BH, Stöhr H. Mutation spectrum of the ABCA4 gene in 335 Stargardt disease patients from a multicenter German cohort—impact of selected deep intronic variants and common SNPs. Investigative ophthalmology & visual science. 2017;58(1):394-403.
16. 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(7):e0132635.
17. Heidari M. A heterozygous STXBP1 gene de novo in mutation in an Iranian child with epileptic encephalopathy: case report. Acta Medica Iranica. 2019;57(8):518-521.
18. Heidari M, Soleyman-Nejad M, Taskhiri MH, Shahpouri J, Isazadeh A, Ahangari R, Mohamadi AR, Ebrahimi M, Karimi H, Bolhassani M, Karimi Z. Identification of Two Novel Mutations in the ATM Gene from Patients with Ataxia-Telangiectasia by Whole Exome Sequencing. Current Genomics. 2019;20(7):531-4.
19. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. British Journal of Ophthalmology. 2017;101(1):25-30.
20. Fukui T, Yamamoto S, Nakano K, Tsujikawa M, Morimura H, Nishida K, Ohguro N, Fujikado T, Irifune M, Kuniyoshi K, Okada AA. ABCA4 gene mutations in Japanese patients with Stargardt disease and retinitis pigmentosa. Investigative ophthalmology & visual science. 2002;43(9):2819-24.
21. Paloma E, Martínez‐Mir A, Vilageliu L, Gonzàlez‐Duarte R, Balcells S. Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies. Human mutation. 2001;17(6):504-10.
22. Biswas EE. Nucleotide binding domain 1 of the human retinal ABC transporter functions as a general ribonucleotidase. Biochemistry. 2001;40(28):8181-7.
23. Sun H, Smallwood PM, Nathans J. Biochemical defects in ABCR protein variants associated with human retinopathies. Nature genetics. 2000;26(2):242-6.
24. Tsybovsky Y, Wang B, Quazi F, Molday RS, Palczewski K. Posttranslational modifications of the photoreceptor-specific ABC transporter ABCA4. Biochemistry. 2011;50(32):6855-66.
25. Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP. Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Investigative ophthalmology & visual science. 2001;42(10):2229-36.
26. Battu R, Verma A, Hariharan R, Krishna S, Kiran R, Jacob J, Ganapathy A, Ramprasad VL, Kumaramanickavel G, Jeyabalan N, Ghosh A. Identification of novel mutations in ABCA4 gene: clinical and genetic analysis of Indian patients with Stargardt disease. BioMed research international. 2015;2015.
27. Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, Roman AJ, Sumaroka A, Steinberg JD, Jacobson SG, Stone EM. ABCA4 disease progression and a proposed strategy for gene therapy. Human molecular genetics. 2009;18(5):931-41.
IssueVol 61 No 6 (2023) QRcode
Stargardt syndrome ATP binding cassette subfamily a member 4 (ABCA4) gene Retinitis pigmentosa Whole exome sequencing

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How to Cite
Mohebi M, Heidari M, Heidari M. Identification of Two Novel Mutations in ABCA4 Gene in a Patient With Stargardt Disease. Acta Med Iran. 2023;61(6):329-333.