Journal List > J Korean Med Sci > v.34(Suppl 1) > 1125314

Kim, Joo, Seong, Kim, Park, Park, and Woo: Genetic Mutation Profiles in Korean Patients with Inherited Retinal Diseases



Because of genetically and phenotypically heterogenous features, identification of causative genes for inherited retinal diseases (IRD) is essential for diagnosis and treatment in coming gene therapy era. To date, there are no large-scale data of the genes responsible for IRD in Korea. The aim of this study was to identify the distribution of genetic defects in IRD patients in Korea.


Medical records and DNA samples from 86 clinically diagnosed IRD patients were consecutively collected between July 2011 and May 2015. We applied the next-generation sequencing strategy (gene panel) for screening 204 known pathogenic genes associated with IRD.


Molecular diagnoses were made in 38/86 (44.2%) IRD patients: 18/44 (40.9%) retinitis pigmentosa (RP), 8/22 (36.4%) cone dystrophy, 6/7 (85.7%) Stargardt disease, 1/1 (100%) Best disease, 1/1 (100%) Bardet-Biedl syndrome, 1/1 (100%) congenital stationary night blindness, 1/1 (100%) choroideremia, and 2/8 (25%) other macular dystrophies. ABCA4 was the most common causative gene associated with IRD and was responsible for causing Stargardt disease (n = 6), RP (n = 1), and cone dystrophy (n = 1). In particular, mutations in EYS were found in 4 of 14 autosomal recessive RP (29%). All cases of Stargardt disease had a mutation in the ABCA4 gene with an autosomal recessive trait.


This study provided the distribution of genetic mutations responsible for causing IRD in the Korean patients. This data will serve as a reference for future genetic screening and treatment for Korean IRD patients.

Graphical Abstract



Inherited retinal diseases (IRD) are characterized by progressive dysfunction of neural retina or retinal pigment epithelium (RPE) which include various subtypes, such as rod-dominant abnormality (rod-cone dystrophy [retinitis pigmentosa, RP]), cone-dominant abnormality (cone or cone-rod dystrophy), macular dystrophy (Stargardt disease, Best macular dystrophy, pattern dystrophy, Sorsby fundus dystrophy, etc.), abnormality of photoreceptors and bipolar cells (X-linked retinoschisis, congenital stationary night blindness [CSNB], etc.), vitreoretinopathies (Wagner syndrome, Stickler syndrome, etc.), and hereditary choroidal diseases.12
Different IRDs may have similar phenotypic characteristics through different genetic mutations. On the other hand, identical genetic mutations may result in IRDs with different phenotypic features.123 Because of the genetic and phenotypic heterogeneity, identification of the causative genetic variants linked to IRD is needed for the accurate diagnosis and treatment of these patients. As the next-generation sequencing (NGS) technology, which can save tremendous cost and time as compared to the previous technologies, has rapidly developed, identification of the causative genes responsible for IRD has dramatically improved.4567891011 To date, about 270 genes have been identified as the cause of IRD in accordance with RetNet database ( The causative genes for IRD are also known to have ethnic and regional differences.5 However, research on this field is mostly based on data obtained from the western population, and no genomic or clinical studies on overall IRD has been previously reported from Korea. In the present study, we have performed molecular analyses involving 86 Korean IRD patients using NGS technology to identify the distribution of the causative genes and mutations linked to IRD in these patients.



We examined 86 Korean patients diagnosed with IRD from unrelated families who visited the Department of Ophthalmology of Seoul National University Bundang Hospital between July 2011 and May 2015 and agreed to participate in the study.
Retinal specialists made the diagnoses of all the IRD cases based on comprehensive ophthalmologic examinations. All the patients underwent visual acuity measurements, slit-lamp biomicroscopy, fundus photography, optical coherence tomography (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany), and full-field standard electroretinography (VERIS II; Electro-Diagnostic Imaging Inc., San Francisco, CA, USA) according to the protocol of the International Society for Clinical Electrophysiology of Vision.12 Additional examinations such as fundus autofluorescence (Spectralis HRA; Heidelberg Engineering) and electrooculography were performed in selected cases. Pedigrees were constructed based on interviews with the patients. Peripheral blood samples were obtained from all the patients for DNA extraction.
A total of 86 clinically diagnosed IRD patients, including 44 RP, 22 cone dystrophy, 7 Stargardt disease (STGD), 8 macular dystrophy, 1 Best disease, 1 Bardet-Biedl syndrome, 1 CSNB, 1 choroideremia, and 1 occult macular dystrophy were included in the study.

Comprehensive custom gene panel design

We previously reported the development of a custom capture panel of 204 known and candidate genes linked to IRD.13 These genes were selected from RetNet ( and NEIBank (, and RetinaCentral ( (Supplementary Table 1). A total of 204 genes were covered for all coding exons, 5′ and 3′ untranslated regions (UTRs), and each exon flanked alternative splicing areas.

Library preparation and targeted sequencing

The construction of pre-capture libraries (Illumina, Inc., San Diego, CA, USA) and capture process (Roche NimbleGen, Madison, WI, USA) was performed according to the manufacturer's protocols. The captured libraries were sequenced using Illumina HiSeq 2000 using the paired-end (2100 bp) program (Illumina, Inc.).

Bioinformatical analysis

Burrows-Wheeler Aligner was used to align the sequence reads in the human hg19 reference genome. The variants were annotated using GATK packages, SAMtools, and Dindel. The detected variants were annotated using ANNOVAR. NextGENe software (SoftGenetics, State College, PA, USA) was used for the analysis. The 1,000 Genome database, dbSNP137, and the National Heart, Lung and Blood Institute (NHLBI) Exome Sequencing database were used to filter out the common variants. The Human Gene Mutation Database professional database was used to search the known pathogenic mutations. To predict the functional significance of missense variants in programs predicting, amino acid conservation score (SIFT, Polyphen, and MutationTaster) was used. Variant prioritization was performed as described in the previous report.13 Briefly, the variants were selected in case they were not reported in the 1,000 Genome, dbSNP, or NHLBI Exome Sequencing databases or had low frequencies (< 1%) in the Korean population. The variants with less than 30% heterozygous reads or less than 80% homozygous reads were excluded.
The clinical significance of each variant was classified according to the recent recommendations of the American College of Medical Genetics and Genomics (ACMG) on standards for interpretation and reporting of sequence variations: pathogenic, likely pathogenic, uncertain significance, benign, and likely benign variant.14 We primarily used the automated classification by the Intervar and determined the clinical significance via adjustment by manual review.15 All the variants reported in this paper were further confirmed by Sanger sequencing. The disease-causing variants were predicted in consideration with the clinical inheritance pattern and clinical characteristics of each gene.

Ethics statement

The Institutional Review Board (IRB) of Seoul National University Bundang Hospital approved the study protocols (IRB approval No. B-1901-519-103). All patients were fully informed of the purpose and procedures of this study, and written consent was obtained from each participant. All procedures used in this study adhered to the tenets of the Declaration of Helsinki.


The mean coverage of depth per subject was ranged 177–385 folds and 99.6% of the entire region was sequenced at least 10-fold coverage of depth. Overall, the pathogenic mutations in the causative genes were detected in 38/86 (44.2%) of the patients with IRD. Specifically, pathogenic mutations were identified in 18/44 (40.9%) RP, 8/22 (36.4%) cone dystrophy, 6/7 (85.7%) STGD, 2/8 (25%) macular dystrophy, 1/1 (100%) Best disease, 1/1 (100%) Bardet-Biedl syndrome, 1/1 (100%) CSNB, and 1/1 (100%) choroideremia. No causative gene was found for 1 case of occult macular dystrophy (Table 1).
Table 1

Detection rate of causative gene mutations

Diseases Total Detect, No. (%)
Retinitis pigmentosa 44 18 (40.9)
Cone dystrophy 22 8 (36.4)
Stargardt disease 7 6 (85.7)
Others 13 6 (46.2)
Macular dystrophy 8 2 (25)
Best disease 1 1 (100)
Retinitis pigmentosa associated with Bardet-Biedl syndrome 1 1 (100)
Congenital stationary night blindness 1 1 (100)
Choroideremia 1 1 (100)
Occult macular dystrophy 1 0 (0)
Total 86 38 (44.2)
Of the 18 RP cases where the causative genes were identified, pathogenic mutations were detected in 2 cases of RHO, and 1 case of RP1 in 3 autosomal dominant RP (adRP) patients; and 4 cases of EYS, 3 cases of PDE6B, 2 cases of USH2A, PDE6A in each, and 1 case of ABCA4, RP1L1, IMPG2 in each of the 14 autosomal recessive RP (arRP) patients. Mutation in RP2 was detected in 1 case of X-linked RP. All the RP patients presented no signs of systemic symptoms suggesting syndromic RP. Of the 8 patients with cone dystrophy, 2 cases of GUCY2D and 1 case of PROM1 mutations were detected in 3 autosomal dominant cone dystrophy patients. In 4 patients with autosomal recessive cone dystrophy, mutations in ABCA4, PDE6C, GNAT2, and CNGA3 were detected. Mutation in CACNA1F was detected in 1 case of X-linked cone dystrophy. During the follow-up period, all the patients with cone dystrophy had decreased color vision, visual acuity at daytime and decreased photopic response without night-time visual disturbance nor abnormal scotopic response on electroretinography. Although PROM1 p.R373C is a well-known mutation of STGD, the patient with PROM1 p.R373C mutation who was diagnosed as cone dystrophy in this study also showed characteristic features of cone dystrophy. Six cases of autosomal recessive STGD were identified to have mutations in ABCA4. Among 2 patients with unspecified macular dystrophy, 1 case of PRPH2 mutation with autosomal dominant pattern and 1 case of RGS9BP mutation with an autosomal recessive pattern were detected. One case of Best disease, retinitis pigmentosa associated with Bardet-Biedl syndrome, CSNB, and choroideremia had mutations in BEST1, BBS9, TRPM1, and CHM, respectively (Fig. 1 and Table 2). ABCA4 was the most common causative gene in our cohort that was identified in 8 IRD cases including RP (1 case), cone dystrophy (1 case), and STGD (6 cases). Seventeen family samples including 6 patients (2 cone dystrophy, 1 macular dystrophy, 3 Stargardt disease), were additionally analyzed with Sanger sequencing. The result showed that all the 6 patients have compound heterozygous mutations.
Fig. 1

The percentages of patients having the causative genes out of the entire 86 inherited retinal diseases patient cohort are indicated under the gene names and that out of each disease entity such as RP, CD, and Stargardt is indicated in parenthesis.

AD = autosomal dominant, RP = retinitis pigmentosa, AR = autosomal recessive, XL = X-linked, CD = cone dystrophy.
Table 2

Causative genes and mutations in 38 patients with inherited retinal dystrophy

Diagnosis Inheritance Gene Chromosome Aminoacid change Mutation type CDS ACMG criteria Note
Retinitis pigmentosa (n = 18) AD RHO 3q22.1 p.T17M Missense c.50C>T Likely pathogenic Reported28
AD RHO 3q22.1 p.T17M Missense c.50C>T Likely pathogenic Reported28
AD RP1 8q11.23-q12.1 p.Y485X Nonsense c.1455T>G Pathogenic Reported7
p.C1399Lfs Frameshift c.4196delG Pathogenic Reported29
AR EYS 6q12 p.N3123Tfs Frameshift c.9368delA Pathogenic Novel
p.H2342P Missense c.7025A>C VUS Novel
p.I2188T Missense c.6563T>C Likely pathogenic Reported30
AR EYS 6q12 p.I2188T Missense c.6563T>C Likely pathogenic Reported30
p.G2186E Missense c.6557G>A Likely pathogenic Reported31
AR EYS 6q12 p.Y841delinsXYfs Frameshift c.2522_2523insA Pathogenic Reported31
Splice Noncoding c.2382-2A>T Pathogenic Novel
AR EYS 6q12 p.S1653delinsKXfs Frameshift c.4957_4958insA Pathogenic Reported31
AR PDE6B 4p16.3 p.H557Y Missense c.1669C>T Pathogenic Reported32
AR PDE6B 4p16.3 p.W290XW Nonsense c.869G>A Pathogenic Novel
p.A831AV Missense c.2492C>T Likely pathogenic Novel
AR PDE6B 4p16.3 p.S546_I547del In-frame c.1636_1641delTCCATC Likely pathogenic Novel
p.H557Y Missense c.1669C>T Pathogenic Reported33
AR USH2A 1q41 p.C934W Missense c.2802T>G Likely pathogenic Reported34
p.H68Y Missense c.202C>T VUS Novel
AR USH2A 1q41 p.S1406XS Nonsense c.4217C>A Likely pathogenic Novel
AR PDE6A 5q32 Splice Noncoding c.1407+1G>C Pathogenic Reported35
p.G428GD Missense c.1283G>A Likely pathogenic Novel
AR PDE6A 5q32 Splice Noncoding c.1407+1G>C Pathogenic Reported35
p.G428GD Missense c.1283G>A Likely pathogenic Novel
AR ABCA4 1p22.1 p.Q636K Missense c.1906C>A VUS Novel
p.Q294X Nonsense c.880C>T Likely pathogenic Reported8
AR RP1L1 8p23.1 p.E1559K Missense c.4675G>A VUS Novel
p.P109delinsSPfs Frameshift c.324_325insT Likely pathogenic Reported36
AR IMPG2 3q12.3 Splice Noncoding c.828+1G>A Pathogenic Novel
XL RP2 Xp11.3 p.C108R Missense c.322T>C Likely pathogenic Novel
Cone dystrophy (n = 8) AD GUCY2D 17p13.1 p.F883Lfs Frameshift c.2649delT Likely pathogenic Reported37
p.R964L Missense c.2891G>T VUS Novel
AD GUCY2D 17p13.1 p.R838H Missense c.2513G>A Likely pathogenic Reported38
AD PROM1 4p15.32 p.R373C Missense c.1117C>T Pathogenic Reported39
AR ABCA4 1p22.1 p.L1583P Missense c.4748T>C VUS Reported8
p.Q636K Missense c.1906C>A VUS Novel
AR PDE6C 10q23.33 p.W548L Missense c.1643G>T VUS Novel
p.G836Efs Frameshift c.2507delG Likely pathogenic Novel
AR GNAT2 1p13.3 p.H244Sfs Frameshift c.730_743delCATGAGTCTTTGCA Likely pathogenic Novel
p.R161X Nonsense c.481C>T Likely pathogenic Reported40
AR CNGA3 2q11.2 p.L185V Missense c.553C>G VUS Reporteda
p.R283Q Missense c.848G>A Pathogenic Reported41
XL CACNA1F Xp11.23 p.G1350D Missense c.4049G>A Likely pathogenic Novel
Stargardt disease (n = 6) AR ABCA4 1p22.1 p.R2049fs Frameshift c.6146delA Likely pathogenic Reported8
p.D654N Missense c.1933G>A VUS Reported8
AR ABCA4 1p22.1 p.R2049fs Frameshift c.6146delA Likely pathogenic Reported8
p.T1117A Missense c.3349A>G Likely pathogenic Novel
AR ABCA4 1p22.1 p.C1140W Missense c.3420C>G Likely pathogenic Reported42
p.I1114_M1115delinsM In-Frame c.3342_3344delCAT Likely pathogenic Novel
AR ABCA4 1p22.1 p.C1140W Missense c.3420C>G Likely pathogenic Reported42
p.I1114_M1115delinsM In-Frame c.3342_3344delCAT Likely pathogenic Novel
AR ABCA4 1p22.1 p.L1157X Nonsense c.3470T>G Likely pathogenic Reported8
p.R290Q Missense c.869G>A VUS Novel
AR ABCA4 1p22.1 p.N1588Y Missense c.4762A>T VUS Novel
p.L1157X Nonsense c.3470T>G Likely pathogenic Reported8
Macular dystrophy (n = 2) AD PRPH2 6p21.1 p.P219_P221delinsP In-Frame c.657_662delACGGCC Likely pathogenic Novel
AR RGS9BP 19q13.11 p.E71X Nonsense c.211G>T Likely pathogenic Reported43
p.G205delinsGLfs Frameshift c.614_615insG Pathogenic Novel
Best disease (n = 1) AD BEST1 11q12.3 p.N296K Missense c.888C>A Likely pathogenic Reporteda
Syndromic RP associated with BBS (n = 1) AR BBS9 7p14.3 p.V260G Missense c.779T>G VUS Novel
p.Q807X Nonsense c.2419C>T Likely pathogenic Novel
CSNB (n = 1) AR TRPM1 15q13.3 p.N1304Ifs Frameshift c.3911delA Pathogenic Novel
p.R1133XR Nonsense c.3397C>T Pathogenic Novel
Choroideremia (n = 1) XL CHM Xq21.2 p.Q63X Nonsense c.187C>T Pathogenic Novel
CDS = coding sequence, ACMG = American College of Medical Genetics, AD = autosomal dominant, AR = autosomal recessive, VUS = variant of uncertain significance, XL = X-linked, BBS = Bardet-Biedl syndrome, CSNB = congenital stationary night blindness.
ainformation shown in ClinVar, not in the paper.


In the present study, targeted exome sequencing (gene panel) was employed for the genetic diagnosis of Korean patients with diverse IRD. Molecular diagnosis was possible in 38 (44.2%) cases. To the best of our knowledge, this is the first study to evaluate the diagnostic rate and causative genes responsible for causing diverse IRD among Korean patients using a gene panel approach.
Over the past decades, IRD has been regarded as an ideal target for gene therapy for its monogenic trait, direct accessibility of the affected cells by various surgical procedures, identification of many causative genes, and immune-privileged environment of the retina.3 Recently, the Food and Drug Administration has approved voretigene neparvovec-rzyl (Luxturna®, Spark Therapeutics, Inc., Philadelphia, PA, USA), the first gene therapy using adeno-associated virus as the vector carrying (targeting) RPE65, which is responsible for causing Leber congenital amaurosis and early onset RP.16 Furthermore, numerous clinical trials targeting IRD-causing genes including CNGB3, CNGA3, REP1, CHM, ND4, RS1, MERTK, RPGR, and ABCA4 are in progress.317 To use this genetic treatment modality, identification of the causative genes must precede before establishing a concrete treatment strategy. Considering that the distribution of the causative genes varies among ethnicities, it is necessary to identify the causative genes in various forms of IRD patients in Korea for the upcoming era of gene therapy.
Because RP is the most common form of IRD, genetic studies of IRD have mainly focused on the different mutations in RP.18 To date, 71 causative genes and loci have been identified to be linked to RP (RetNet []). In a previous study involving parallel sequencing of 53 targeted RP genes in 62 non-syndromic Korean patients, casual variants were detected in 50% of the patients.7 In that study, PRPF31 (30%), RHO (20%), and RP1 (20%) were the frequently affected genes in adRP, whereas EYS (40%) and PDE6B (40%) were the frequently affected genes in arRP. We currently identified 18/44 (40.9%) causative gene mutations in the overall RP patients, including RHO (67%) in adRP and EYS (29%) in arRP. Our results are consistent with other recent studies conducted in east Asia demonstrating a higher incidence of EYS mutation in arRP than in the studies conducted among the Caucasians.7919202122 In terms of X-linked RP, RP2 variant was identified uniquely in both the Korean studies, including ours, instead of RPGR which is thought to be the most common causative gene for X-linked RP. The reason for this low detection rate of RPGR in the Korean studies might be due to the ethnic difference or the repetitive purine-rich ORF15 region, a mutation hotspot in RPGR, which is poorly covered using NGS.7
Mutations in five genes (ELOVL4, PROM1, PRPH2, BEST1, and ABCA4) have been reported to be responsible for STGD or Stargardt-like disease. About 47%−96% of the patients with clinically diagnosed STGD were reported to have pathogenic mutations identified, and most of the cases showed autosomal recessive ABCA4 mutations.4102324 The reason for a relatively higher detection rate of the causative genes in STGD than in the other IRDs might be due to the characteristic distinctive features of STGD−choroidal silence sign in fundus fluorescein angiography. This implies that the fine distinction among the different phenotypes is important for the differential diagnosis of IRD. Especially in Asia, the causative genes of STGD other than ABCA4 are rarely found.232526 In a recent study that included clinically diagnosed Korean STGD patients, 17 out of 24 (70.8%) patients were detected to have ABCA4 mutations.8 No potential mutations in the ELOVL4 and PROM1 were, however, found. Similarly, we have detected ABCA4 mutations in 6 of 7 (85.7%) Korean STGD patients and no other 4 STGD-associated genes were found.
Mutations in the KCNV2, CNGB3, and ABCA4 were reported to be the common causative factors of autosomal recessive cone dystrophy, whereas, GUCY2D, CRX, and GUCA1A were accounted for more than half of the genetically identified cases of autosomal dominant cone dystrophy.127 Till date, there is no report of a genetic study with cone dystrophy in Korea. We have identified the causative genes in 8 (36.4%) out of 22 Korean cone dystrophy patients with a high rate of detection of the known causal genes.
The current study could not identify any possible causative genes in about 56% of the cases. Several reasons could explain this low detection rate. First, uninvolved genes or non-exon sequences in our diagnostic panel or unknown causative genes for IRD may exist. Second, ethnic differences, as mentioned, might contribute to the presence of undiscovered Asia-specific causative genes and pathogenic variants linked to IRD. In particular, there is a possibility that specific causative genes and pathogenic variants for IRD exists in Korean population. Third, genomic structural variants and genomic rearrangements affecting more than 50 bp are not detectable by whole exome sequencing or gene panel, unlike whole genome sequencing. The hospital-based retrospective design is also a limitation of the study. Our data might have been affected by selection bias, and hence, might not reflect the true prevalence and genetic association in IRD in the Korean population. However, we have enrolled consecutive IRD patients who were referred from the local clinics without imposing any exclusion criteria. Thus, we have collected crude data on the prevalence and distribution of genetic mutations among the IRD patients in the Korean population. Further population-based studies are necessary to reveal the detailed genetic epidemiology of IRD in the Korean population.
In conclusion, to date, the present study has screened the largest sample of Korean patients diagnosed with different types of IRD and described the relevant genetic characteristics in the cohort. Considering that different subtypes of IRD are genetically and phenotypically heterogeneous and the causative genes of IRD have ethnic differences, our data will serve as a basis for understanding the genetic distribution and characteristics of the Korean IRD patients.


Funding This study was supported by a research grant from the Seoul National University Bundang Hospital (grant No. 02-2017-059); the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science, and Technology (grant No. 2012R1A1A2006958); and the NRF grant from the Ministry of Science, ICT, and Future Planning (MSIP) (grant No. 2016R1D1A1B03934724, 2017R1A2B2011436 and 2019R1C1C1009345). The funding organizations had no role in the design or conduct of the study.

Disclosure The authors have no potential conflict of interest to disclosure.

Author Contributions

  • Conceptualization: Woo SJ, Park SS.

  • Data curation: Woo SJ, Park KH, Seong MW, Park SS, Joo K.

  • Formal analysis: Kim MS, Joo K, Seong MW.

  • Funding acquisition: Woo SJ, Seong MW, Park SS, Joo K.

  • Investigation: Woo SJ, Seong MW, KIM MJ, Park SS.

  • Methodology: Seong MW, Park SS.

  • Validation: Joo K, Woo SJ, Seong MW, Park SS.

  • Writing - original draft: Kim MS, Joo K.

  • Writing - review & editing: Kim MS, Joo K, Woo SJ, Seong MW, Park KH, Park SS.


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Supplementary Table 1

Two hundred four inherited retinal diseases related genes selected for targeted sequencing