Mutations In ABCA4 Gene Research Articles

Generation of two induced pluripotent stem cell lines (LVPEIi007-B, LVPEIi008-B) from patients harboring homozygous mutation in ABCA4 (c.6088C>T) using non-integrative Sendai virus-based approach

Mutations in ABCA4 gene leads to the most common form of an inherited retinal disease namely, the Stargardt disease, type 1. Here, we report the generation of two different patient-specific induced pluripotent stem cell lines (LVPEIi007-B and LVPEIi008-B), carrying an identical homozygous mutation, (c.6088C>T) within the exon 44 of ABCA4 gene. These lines were generated by the reprogramming of patient-specific dermal fibroblasts, using the integration-free, Sendai viral vectors. Both lines were stably expanded and expressed the stemness and pluripotency markers, differentiated into cell types of all three germ layers, and maintained a normal karyotype.

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.

Clinical and Genetic Correlations of Inherital Retinal Disease with Mutations in the ABCA4 Gene by Patients of the Russian Population

Aim: to study genotype-phenotype correlations in patients with inherited retinal diseases with mutations in ABCA4 gene in Russian Federation.Patients and methods. 21 patients from Russian population aged from 7 to 51 years old (mean age 20 ± 11 years with best-corrected visual acuity from 0,02 to 0,6 (0,14 ± 0,11) with ABCA4-associated retinopathy, verified by molecular genetics methods. All patients besides standard ophthalmic examination and photodocumentation were performed Spectral-Domain OCT and fundus autofluorescence on Spectralis ®HRA+OCT (Heidelberg Engineering, Germany). Full-field electroretinogram (ERG), 30-Hz flicker ERG and macular chromatic ERG (MERG) to red stimulus were recorded on electroretinographic system MBN (MBN, Russia). (Russia) Molecular genetic studies were performed using Next Generation Sequencing (NGS) and Sandger direct sequencing. Results: In ABCA4-associated Stargardt disease 1 type (STGD1) genotype [p.L541P, p.A1038V] of «frequent» mutations was revealed in 9 patients, in 2 cases in was associated another “frequent” mutation p.G1961E. In 4 patients with genotype [p.L541P, p.A1038V] “severe” phenotype of Stargardt disease was found: with large defect of the ellipsoid zone and large zone of central reduced autofluorescence, severely subnormal macular ERG (MERG) to red stimulus and subnormal 30 Hz flicker and full-field maximal ERG. In one patient with these mutations in homozygous state ABCA4-associated cone-rod dystrophy (CORD3, clinically looking alike secondary retinal dystrophy is diagnosed. In 2 patients with genotype [p.L541P, p.A1038V] and mutation p.G1961E was found mild phenotype. One patient with homozygous mutation p.R653C autosomal recessive ABCA4-associated retinitis pigmentosa (RP19) was diagnosed. Clinical picture and autofluorescence were polymorphic in all patients.Conclusions. Our study with ophthalmological, molecular genetics and instrumental methods widens the spectrum of clinical signs of inherited eye diseases associated with mutations in АВСА4 gene, widens the spectrum mutations in Russian Federation and reveals clinicо-genetic genotype-phenotype correlations.

Molecular analysis of ABCA4 gene in an Iranian cohort with Stargardt disease

IntroductionThe most prevalent cause of autosomal recessive juvenile maculopathy is a retinal disease known as Stargardt disease (STGD1; OMIM 248200). The aim of this prospective, this study was performed to investigate the spectrum of mutations in ABCA4 gene in an Iranian Stargardt (STGD1) cohort. MethodsSeventeen families with at least one patient affected with STGD1 were included in the study for molecular analysis. Whole exome sequencing was performed for genotype determination in one patient. DNA Sanger sequencing was performed for confirmation of the mutation in the proband and the parents. The identified pathogenic variant was also screened in the other patients enrolled in the study. ResultsRecessive variant c.5882 G > A (p. Gly1961Glu) was found in homozygous and heterozygous forms in the proband and the parents, respectively. The results of short tandem repeat (STR) markers showed that the disease in the family is linked to the ABCA4 gene. This variant was also detected in six unrelated patients in heterozygous form. Conclusionc.5882 G > A (p. Gly1961Glu) is a common variant in Iranian patients with STGD1. The data of the study will improve the molecular insights of the disease in Iranian population and further deep molecular studies on the larger number of patients can provide genetic counseling for the families.

Generation of an induced pluripotent stem cell line from a patient with Stargardt disease caused by biallelic c.[5461–10T>C;5603A>T];[6077T>C] mutations in the ABCA4 gene

Mutations in ABCA4 gene are causative for autosomal recessive Stargardt disease (STGD1), the most common inherited retinal dystrophy. Here, we report the generation of an induced pluripotent stem cell (iPSC) line from a STGD1 patient carrying biallelic c.[5461–10T>C;5603A>T];[6077T>C] mutations in the ABCA4 gene. Episomes carrying OCT4, SOX2, KLF4, L-MYC, LIN28 and mp53DD were employed for the reprogramming of patient-derived fibroblasts. This iPSC line expressed comparable pluripotency markers as in a commercially available human iPSC line, displayed normal karyotype and potential for trilineage differentiation, and were negative for both reprogramming episomes and mycoplasma test.

Formulation and efficacy of ECO/pRHO-ABCA4-SV40 nanoparticles for nonviral gene therapy of Stargardt disease in a mouse model

It is still a challenge to develop gene replacement therapy for retinal disorders caused by mutations in large genes, such as Stargardt disease (STGD). STGD is caused by mutations in ABCA4 gene. Previously, we have developed an effective non-viral gene therapy using self-assembled nanoparticles of a multifunctional pH-sensitive amino lipid ECO and a therapeutic ABCA4 plasmid containing rhodopsin promoter (pRHO-ABCA4). In this study, we modified the ABCA4 plasmid with simian virus 40 enhancer (SV40, pRHO-ABCA4-SV40) for enhanced gene expression. We also prepared and assessed the formulations of ECO/pDNA nanoparticles using sucrose or sorbitol as a stablilizer to develop consistent and stable formulations. Results demonstrated that ECO formed stable nanoparticles with pRHO-ABCA4-SV40 in the presence of sucrose, but not with sorbitol. The transfection efficiency in vitro increased significantly after introduction of SV40 enhancer for plasmid pCMV-ABCA4-SV40 with a CMV promoter. Sucrose didn't affect the transfection efficiency, while sorbitol resulted in a fluctuation of the in vitro transfection efficiency. Subretinal gene therapy in Abca4−/− mice using ECO/pRHO-ABCA4 and ECO/pRHO-ABCA4-SV40 nanoparticles induced 36% and 29% reduction in A2E accumulation respectively. Therefore, the ECO/pABCA4 based nanoparticles are promising for non-viral gene therapy for Stargardt disease and can be expended for applications in a variety of visual dystrophies with mutated large genes.

Clinical and genetic analysis of the ABCA4 gene associated retinal dystrophy in a large Chinese cohort

ABCA4 gene associated retinal dystrophies (ABCA4-RD) are a group of inherited eye diseases caused by ABCA4 gene mutations, including Stargardt disease, cone-rod dystrophy and retinitis pigmentosa. With the development of next-generation sequencing (NGS), numerous clinical and genetic studies on ABCA4-RD have been performed, and the genotype and phenotype spectra have been elucidated. However, most of the studies focused on the Caucasian population and limited studies of large Chinese ABCA4-RD cohorts were reported. In this study, we summarized the phenotypic and genotypic characteristics of 129 Chinese patients with ABCA4-RD. We found a mutation spectrum of Chinese patients which is considerably different from that of the Caucasian population and identified 35 novel ABCA4 mutations. We also reported some rare and special cases, such as, pedigrees with patients in two generations, patients diagnosed with cone-rod dystrophy or retinitis pigmentosa, patients with subretinal fibrosis and patients with preserved foveal structure. At the same time, we focused on the correlation between the genotypes and phenotypes. By the comprehensive analysis of multiple clinical examinations and the application of multiple regression analysis, we proved that patients with two “null” variants had a younger onset age and reached legal blindness earlier than patients with two “none-null” variants. Patients with one or more "none-null" variants tended to have better visual acuity and presented with milder fundus autofluorescence changes and more preserved rod functions on the full-field electroretinography than patients with two “null” variants. Furthermore, most patients with the p.(Phe2188Ser) variant shared a mild phenotype with a low fundus autofluorescence signal limited to the fovea and with normal full-field electroretinography responses. Our findings expand the variant spectrum of the ABCA4 gene and enhance the knowledge of Chinese patients with ABCA4-RD.

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies.

Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy.

Retinal oxidative damage, associated with an ATP-binding cassette, sub-family A, member 4, also known as ABCA4 gene mutation, has been implicated as a major underlying mechanism for Stargardt disease/fundus flavimaculatus (STG/FF). Recent findings indicate that saffron carotenoid constituents crocins and crocetin may counteract retinal oxidative damage, inflammation and protect retinal cells from apoptosis. This pilot study aimed to evaluate central retinal function following saffron supplementation in STG/FF patients carrying ABCA4 mutations. Methods: in a randomized, double-blind, placebo-controlled study (clinicaltrials.gov: NCT01278277), 31 patients with ABCA4-related STG/FF and a visual acuity >0.25 were randomly assigned to assume oral saffron (20 mg) or placebo over a six month period and then reverted to P or S for a further six month period. Full ophthalmic examinations, as well as central 18° focal electroretinogram (fERG) recordings, were performed at baseline and after six months of either saffron or placebo. The fERG fundamental harmonic component was isolated by Fourier analysis. Main outcome measures were fERG amplitude (in µV) and phase (in degrees). The secondary outcome measure was visual acuity. Results: supplement was well tolerated by all patients throughout follow-up. After saffron, fERG amplitude was unchanged; after placebo, amplitude tended to decrease from baseline (mean change: −0.18 log µV, p < 0.05). Reverting the treatments, amplitude did not change significantly. fERG phase and visual acuity were unchanged throughout follow-up. Conclusions: short-term saffron supplementation was well tolerated and had no detrimental effects on the electroretinographic responses of the central retina and visual acuity. The current findings warrant further long-term clinical trials to assess the efficacy of saffron supplementation in slowing down the progression of central retinal dysfunction in ABCA4-related STG/FF.

Mutation analysis of the ABCA12 gene in two families with autosomal recessive congenital ichthyosis

Objective To detect mutations of the ABCA12 gene in 2 Chinese families with autosomal recessive congenital ichthyosis (ARCI) . Methods According to the typical clinical manifestations, two probands were diagnosed with ARCI. DNA was extracted from the peripheral blood samples collected from the patients and their parents. High-throughput sequencing was conducted by using multi-gene array for genetic skin disorders to determine mutation sites in the probands, and then DNA isolated from the probands and their parents were bidirectionally verified by Sanger sequencing. Results Two compound heterozygous mutations (c.2759A>G and c.7004A>G) in the ABCA12 gene were found in the proband 1, and another two compound heterozygous mutations (c.6163_6164insT and c.7406G>A) were identified in the proband 2. The parents of the two probands were heterozygous carriers of one of the two mutations in the ABCA12 gene. Function prediction for the 4 mutations showed that all of the 3 missense mutations (c.2759A>G, c.7004A>G and c.7406G>A) may exert pathogenic effect, and fragmin encoded by the frameshift mutation c.6163_6164insT may also affect protein function. c.2759A>G and c.6163_6164insT were newly identified mutation sites. Conclusion The compound heterozygous mutations in the ABCA12 gene are the causative mutations responsible for ARCI in the two probands of the two pedigrees. Key words: Ichthyosis; DNA mutational analysis; High-throughput nucleotide sequencing; Autosomal recessive congenital ichthyosis; ABCA12 gene; Multi-gene array for genetic dermatology; Compound heterozygous mutation

ABCA4 mutations and phenotype of different hereditary retinopathies in 3 pedigrees

Objective: To analyze the relationship between genotype and phenotype of different types of hereditary retinopahty caused by ABCA4 gene. Method: Three (3) pedigrees that carried mutations on ABCA4 gene as determined through the second generation sequencing technology were selected from the patients diagnosed with hereditary retinal disease in Ningxia Eye Hospital between Januaryand September 2016. The clinical features of patients and other family members of them were collected and analyzed with complete ophthalmic examinations including visual acuity, best corrected visual acuity, fundus examination, macular OCT, fundus fluorescein angiography and electroretinogram (ERG). The relationship between genotype and phenotype was analyzed. Results: All the 3 pedigrees were autosomal recessive families. Four mutations on ABCA4 gene were detected, the CRD pedigree and the RP pedigress carried a homozygous frameshift mutation respectively. The Stargardt pedigree carried two heterozygous mutations. The onset age of the patients were less than 10 years. The best corrected visual acuity was lower than 0.1 and the macular OCT indicated different levels of macular area atrophy, and the visual electrophysiological changes varied from completely normal to significantly reduced visual stem cell function in different cases. Conclusions: The patients with hereditary retinal disease that carried ABCA4 gene mutations were featured with characteristics of early onset age, rapid progress and severe visual impairment. The second generation sequencing technique has the advantages of rapidness and high efficiency in the diagnosis of hereditary retinal disease. (Chin J Ophthalmol, 2018, 54:775-781).

Clinical and Genetic Characteristics Analysis of Korean Patients with Stargardt Disease Using Targeted Exome Sequencing

Purpose: To investigate genetic mutations in Korean patients with Stargardt disease (STGD) using exome sequencing, and to analyze the correlations between genetic mutations and clinical phenotypes. Methods: Peripheral venous blood was obtained from 24 clinically diagnosed Korean STGD patients, followed by extraction of genomic DNAs. Using exome sequencing we investigated gene mutations for the adenosine triphosphate-binding cassette, subfamily A, member 4 (ABCA4) elongation of very-long-chain fatty acids 4 (ELOVL4), and prominin 1 (PROM1), and confirmed gene mutations by the direct sequencing of polymerase chain reaction products. Results: ABCA4 mutations were confirmed in 17 of 24 patients, and 12 novel mutations were identified. ELOVL4 and PROM1 gene mutations were not identified in this study. We also identified 16 previously reported mutations related to STGD1. In patients whose disease symptoms occurred before 20 years of age, visual acuity was poorer and atrophic flecks were more frequently found. In addition, more ABCA4 mutations were found in patients who had choroidal silence or atrophic flecks. Conclusions: Novel ABCA4 gene mutations were found in Korean patients with STGD1. This study will facilitate better understanding of the relationships between ABCA4 gene mutations and clinical symptoms in Korean patients.

Management Of Stargardt’s Disease Through Ayurvedic Science

Stargardt’s disease is a hereditary disorder of the retina. There is a gradual loss of vision during childhood or adolescence and in a few cases, vision loss may be noticed in adulthood. Involvement of photoreceptor cells presents slow loss of central vision, distorted vision and reduced color vision. Mutations in ABCA4 gene following accumulation of lipofuscin within the retinal pigment epithelium is a causative factor of the disease. Beaten bronze reflex or Snail slime reflex from the macula is the typical clinical presentation.

Next generation sequencing in the diagnosis of Stargardt's disease

Abstract Introduction Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. Patients and methods A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. Results Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2. Conclusions NGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.

Inherited retinal diseases in patients with ABCA4 gene mutations

ABCA4 is one of the main genes which mutations are associated with various inherited retinal diseases (IRD) such as Stargardt disease, cone dystrophy, cone-rod dystrophy, and retinitis pigmentosa. Wide prevalence of IRD, high heterogeneity of ABCA4 gene mutations that lead to impaired function of the protein with varying expressiveness make studying of the clinical and genetic characteristics of retinal diseases relevant for further investigations into pathogenesis, prognosis and outcome of the disease. This article reviews the literature on incidence of IRD caused by mutations in the ABCA4 gene and characteristics of the clinical progression of retinal diseases associated with various types of mutations, and presents analysis of clinical and genetic correlations in terms of the effect the mutation has on the structure or function of the protein.

Stargardt Disease.

Stargardt disease (STGD) is one of the most common macular dystrophies in young adults. It progresses slowly. Its prevalence is about 1:8000-10,000. Age of onset is a surrogate marker: The earlier the onset, the more severe the disease course. Onset usually occurs in childhood or early adolescence, at about 10-15 years of age. Vision is between about 20/70 and 20/200. The fundus shows a bull's eye pattern or beaten-bronze appearance, with or without yellowish flecks (fundus flavimaculatus). Fluorescein angiography may show dark choroid in about 80% of cases. On fundus autofluorescence (FAF), newer flecks appear hyperautofluorescent (hyperAF); older ones become progressively more hypoAF with time. Some flecks are surrounded by a ring of decreased AF. Peripapillary sparing is one the characteristics of Stargardt disease, but this area can be involved in about 2-7% of cases. The reason for this sparing is unclear; this area may be more resilient to the deleterious effect of ABCA4 gene mutation, and there might be a more favorable RPE photoreceptor ratio, resulting in less lipofuscin build-up, in the presence of a thicker overlying peripapillary retinal nerve fiber layer. Patients with Stargardt disease should avoid bright light and excessive vitamin A.

Experimental studies on medical treatments of retinal dystrophies with a particular focus on ABCA4 retinopathies.

Retinal dystrophies are a group of hereditary diseases varying in clinical and etiological aspects. The most common central retinal dystrophy is Stargardt's disease, which is mainly caused by mutations in the ABCA4 gene. Dysfunction of the ABCA4 gene product leads to accumulation of toxic metabolites of the visual cycle and consequently to the loss of photoreceptors and surrounding retinal pigment epithelial cells. This study summarizes various pharmacological attempts aimed at slowing the progression of retinal dystrophies, especially ABCA4 retinopathies.

Quantifying the Rate of Ellipsoid Zone Loss in Stargardt Disease

To determine a reliable method of using the ellipsoid zone (EZ) on optical coherence tomography (OCT) to track disease progression in Stardgardt disease (STGD). Retrospective reliability study. STGD patients with genetically confirmed ABCA4 gene mutations seen at the Wilmer Eye Institute with follow-up visits separated by at least 12months were identified. Spectral-domain optical coherence tomography (SD-OCT) macula volume scans centered at the fovea and fundus autofluorescence (FAF) images were obtained. The area of EZ loss was calculated from the SD-OCT and the area of retinal pigment epithelium (RPE) loss from the FAF. Scans were reanalyzed by the primary grader to assess intragrader reliability, and reanalyzed by a second grader to assess intergrader reliability. Sixteen STGD patients (total of 31 eyes) were followed for a mean of 2 years (range 1-4.7 years). The mean rate of EZ loss, 0.31 ± 0.31mm2/year, was similar to the average rate of RPE loss, 0.33 ± 0.38mm2/year. The average area of EZ loss at the initial examination, 4.18 ± 1.91mm2, was larger than the initial area of RPE loss, 2.25 ± 1.66mm2 (P < .01). The absolute difference of the area of EZ loss on test-retest for the first grader was 0.12 ± 0.10mm2, and between graders 0.21 ± 0.21mm2. The intraclass correlation (ICC) of both intragrader and intergrader reliability for EZ loss was excellent at 0.99. Tracking the area of EZ loss on SD-OCT macular volume scans longitudinally is a reliable way of monitoring disease progression in STGD. This could be used as a sensitive anatomic outcome measure in clinical trials related to STGD.

La secuenciación masiva (NGS) como método diagnóstico en la enfermedad de Stargardt

IntroductionStargardt‘s disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. Patients and methodsA report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. ResultsClinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2. ConclusionsNGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.

The spectrum of mutations in the patients presenting with ABCA4-associated Stargardt's disease in a Russian population

Introduction. Stargardt's disease is a hereditary retinal dystrophy characterized by the early manifestation and the progressive deterioration of visual acuity. The spectrum of mutations in the ABCA4 gene associated with this pathology in the Russian Federation has not been fully investigated. Aim. The objective of the present study was to elucidate the spectrum of mutations in the ABCA4 gene in the Russian patients presenting Stargardt's disease. Materials and methods. The study included a total of 38 unrelated patients at the age varying from 6 to 48 (mean 20 ± 8.9) years having the clinically confirmed diagnosis of Stargardt's disease. The search of mutations in DNA extracted from the peripheral blood lymphocytes of the patients was carried out with the use of a set of oligonucleotide primers (Ion Ampliseq Inherited Disease Panel; Life Technologies, USA). The Ion Torrent PGM Sequencer (Life Technologies, USA) was used for the parallel semiconductor sequencing of the gene-coding regions. All the patients underwent the standard ophthalmological examination, electroretinography, optical coherence tomography, and fundus autofluorescence. Results. We established the spectrum of mutations in the ABCA4 gene in the patients of a Russian population suffering from autosomal-recessive Stargardt's disease. We identified 45 alleles responsible for the development of this condition. 14 of them had been earlier described in the Russian patients while 19 were discovered for the first time in this country although they had been known to occur in other populations. Moreover, we described 12 novel heterozygous variations, viz. c.230T&gt;A (rs61748527), c.4956T&gt;G (rs61750561), c.2820&gt;G (rs81749445). c.5226delT, c.2537A&gt;T, c.57353T, c.893delG, c.702 insATC, c.3896T&gt;G, c.1356delA, c.1341delGAT, and c.231insGAAAA. Discussion. The study has revealed the rather variable phenotype in the patients presenting with ABCA4-associated Stargardt's disease. A wide variety of mutations were shown to be responsible for the difference of the clinical picture of this condition in individual patients. The comparison of the genotypes and the phenotypes has demonstrated the differential effect of the concrete mutations. Conclusion. The spectrum of mutations in the patients presenting with ABCA4-associated Stargardt's disease in the surveyed Russian population is different from that in other populations. We have revealed 12 previously unknown mutations; moreover 19 mutations have been described for the first time in this country although they had been previously known to occur in other populations.