M.E. Ivanova1, V.V. Kadyshev2, D.S. Atarshchikov3, I.V. Zolnikova4, N.P. Akchurina4, N.K. Serova5, F.A. Konovalov6, E.R. Lozier6, E.A. Pomerantseva7, N.V. Vetrova7, D. Barh8, L.M. Balashova9, J.M. Salmasi10 1 LLC “Oftalmic”, Moscow, Russian Federation 2 Research Centre for Medical Genetics, Moscow, Russian Federation 3 Central Clinical Hospital under Presidential Affairs, Moscow, Russian Federation 4 Moscow Helmholtz Research Institute of Eye Diseases, Moscow, Russian Federation 5 N.N. Burdenko National Medical Research Center of Neurosurgery, Moscow, Russian Federation 6 Independent Clinical Bioinformatics Laboratory, Moscow, Russian Federation 7 Center for Genetics and Reproductive Medicine “Genetiko”, Moscow, Russian Federation 8 Institute of Integrative Omics and Applied Biotechnology (IIOAB), Bangalore, India 9 Non-profit partnership International Scientific and Practical Center for the Proliferation of Tissues of Russia, Moscow, Russian Federation 10Pirogov Russian National Research Medical University, Moscow, Russian Federation The article describes the clinical case of optic atrophy due to a homozygous mutation in exon 3 of the C19orf12 gene (chr19: 30193863AACAGCCCCCCG> A, rs515726204), the frequency of which in the ExAC control sample is 0.0074. With this mutation, a frameshift occurs at 69-th position (p.Gly69fs, NM_001031726.3), which usually leads to neurodegeneration with the brain iron accumulation (NBIA), type 4 (OMIM: 614298). In described clinical case the main complaint of patient was visual impairment, with magnetic resonance imaging patient revealed only the expansion of the sellar fossa. The vision of 7-year-old boy decreased significantly for 2 years without any apparent reasons, spectacle correction did not give an improvement in vision to 100%. During the examination partial atrophy of the optic nerves was revealed, consultations were conducted with a neurologist, neurophthalmologist. Hyperreflexia, gait changes, and a slight delay in speech development were also revealed. No other clinical neurological symptoms were observed. The article describes a detailed ophthalmic clinical picture, discusses diagnostic and therapeutic tactics. Keywords: optic nerve atrophy, neurodegeneration with the brain iron accumulation, NBIA, mutation, gene, C19orf12. For citation: Ivanova M.E., Kadyshev V.V., Atarshchikov D.S. et al. Case of phenotype of optic nerve atrophy due to mutation in С19orf12 gene (neurodegeneration with the brain iron accumulation (nbia)). Russian Journal of Clinical Ophthalmology. 2020;20(1):–36. DOI: 10.32364/2311-7729-2020-20-1-33-36.

Изучение спектра мутаций и совершенствование диагностики синдрома Ашера (СА) особо актуальны в связи с разрабатываемыми подходами к генной терапии заболевания. Среди 46 пациентов с признаками СА патогенные мутации выявлены нами у 40 (87%) пациентов. СА I и II типов определены у 26% и 57% пробандов исходной выборки, соответственно. У пациентов с СА I выявлены мутации в генах MYO7A (73%), CDH23 (7%), PCDH15 (7%), и USH1C (13%). Наибольшую частоту показала мутация MYO7A p.Q18*. Описано 6 новых мутаций в гене MYO7A, и две - в гене PCDH15. У пациентов с СА II выявлена 21 мутация гена USH2A, 5 из которых описаны впервые. Наибольшую частоту показала мутация USH2A p.W3955*. У двух пациентов выявлены мутации в генах несиндромального пигментного ретинита RHO и RPGR, что позволило уточнить клинический диагноз. Studying the mutation spectrum and improvement of molecular verification of the Usher syndrome (USH) are of particular relevance as gene therapy emerges. Among 46 patients with signs of Usher syndrome we identified mutations in 40 (85%) patients, establishing a diagnosis of USH1 and USH2 for 26% and 57% of the probands of the initial sample, respectively. Patients with USH1 showed mutations in the MYO7A (73%), CDH23 (7%), PCDH15 (7%), and USH1C (13%) genes. MYO7A p.Q18* mutation showed the highest frequency. We have identified 6 new mutations in the MYO7A gene, and 2 in the PCDH15 gene. In USH2 patients, 21 USH2A gene mutations were identified, 5 of which are novel. The USH2A mutation p.W3955* was most frequent. Two patients showed mutations in the non-syndromic retinitis pigmentosa genes RHO and RPGR, which made it possible to clarify the clinical diagnosis.

Achromatopsia (ACHM) is a rare autosomal recessive disease. Its mutation spectrum is well described in other populations, but the data on ACHM prevalence and features in Russia are insufficient. Purpose . To describe clinically and genetically the Russian cohort of AHCM for the potential use of targeted treatment approaches, including gene therapy. Material and methods . Out of 18 patients with clinical manifestations of ACHM, 10 patients were chosen (6 with no kinship relatedness and 4 with kinship relatedness) aged 12.3 ± 5.8 years. These patients underwent standard ophthalmologic examination: visometry, perimetry, biomicroscopy, ophthalmoscopy, as well as optical coherence tomography, electroretinography, and color test on distinguishing color shades, in order to determine the clinical characteristics of ACHM. Molecular genetic confirmation of the clinical diagnosis was performed by high-performance parallel DNA sequencing. An in silico analysis of pathogenetic pathways of the clinical picture in 10 patients with confirmed ACHM was performed. Results . In the examined Russian patients, previously determined mutations in the CNGA3 and CNGB3 genes were confirmed. The most common mutation was a single nucleotide deletion with a reading frame shift in the 10th exon of the CNGB3 gene; a missense mutation in the 8th exon of the CNGA3 gene was second frequent. One patient had mutations in the CNGA3 and CNGB3 genes. Segregation analysis confirms the autosomal recessive nature of disease inheritance. Mutations in the CNGB3 gene have been observed to lead to more serious clinical manifestations than mutations in CNGA3. Conclusions . The analysis of the Russian ACHM cohort shows that mutations in the CNGA3 and CNGB3 genes are the main cause of the development of the disease. A complete molecular genetic confirmation of the clinical diagnosis has been obtained, which is necessary for prescribing targeted treatment to patients, including gene therapy.

Achromatopsia (ACHM) is a rare autosomal recessive disease. Its mutation spectrum is well described in other populations, but the data on ACHM prevalence and features in Russia are insufficient. Purpose. To describe clinically and genetically the Russian cohort of AHCM for the potential use of targeted treatment approaches, including gene therapy. Material and methods. Out of 18 patients with clinical manifestations of ACHM, 10 patients were chosen (6 with no kinship relatedness and 4 with kinship relatedness) aged 12.3 ± 5.8 years. These patients underwent standard ophthalmologic examination: visometry, perimetry, biomicroscopy, ophthalmoscopy, as well as optical coherence tomography, electroretinography, and color test on distinguishing color shades, in order to determine the clinical characteristics of ACHM. Molecular genetic confirmation of the clinical diagnosis was performed by high-performance parallel DNA sequencing. An in silico analysis of pathogenetic pathways of the clinical picture in 10 patients with confirmed ACHM was performed. Results. In the examined Russian patients, previously determined mutations in the CNGA3 and CNGB3 genes were confirmed. The most common mutation was a single nucleotide deletion with a reading frame shift in the 10th exon of the CNGB3 gene; a missense mutation in the 8th exon of the CNGA3 gene was second frequent. One patient had mutations in the CNGA3 and CNGB3 genes. Segregation analysis confirms the autosomal recessive nature of disease inheritance. Mutations in the CNGB3 gene have been observed to lead to more serious clinical manifestations than mutations in CNGA3. Conclusions. The analysis of the Russian ACHM cohort shows that mutations in the CNGA3 and CNGB3 genes are the main cause of the development of the disease. A complete molecular genetic confirmation of the clinical diagnosis has been obtained, which is necessary for prescribing targeted treatment to patients, including gene therapy.

Background: The complete form of X-linked congenital stationary night blindness (CSNB1A) is a very rare genetic disease caused by mutation in the NYX gene. CSNB1A-associated several mutations in the NYX gene have been reported earlier. Methods: In this case report, we have clinically diagnosed and genetically confirmed a novel mutation associated with CSNB1A in four members of a Russian family. Two male siblings from a family of four siblings (two girls, two boys) with non-progressive stable night blindness since early childhood and high myopia underwent - visual acuity test, perimetry, biomicroscopy, OCT, ophthalmoscopy, electroretinography, color vision Hue test, NGS based whole exome analysis and Sanger sequencing for clinical characterization and genetic confirmation of CSNB. Results: The members are clinically diagnosed and genetically confirmed with CSNB1A. All the patients had a novel frameshift mutation in the NYX gene (c.283delC, p.His95fs, NM_022567.2) that is found to segregate in X-linked manner Conclusions: This is probably the first case report with a novel mutation from Russia associated with CSNB1A.

The complete form of X-linked congenital stationary night blindness (CSNB) is a rare genetic disease caused by a mutation in the NYX gene. CSNB is associated with the mutations taking place in 17 genes, whilst its CSNB1A form is caused by the mutations in the NYX gene, which were characterized earlier, although nothing had been reported so far about the Russian founder principle. The paper analyzes the pathogenetic mechanisms in a family with diagnosed CSNB1A and a new genetically confirmed mutation in the NYX gene in four members of one Russian family. Two brothers of the four siblings (two boys, two girls) with congenital stationary night blindness, diagnosed in early childhood, and high myopia underwent a standard ophthalmic examination, supplemented with OCT, electroretinography and color blind test with tables by Rabkin and Farnsworth test, whereupon they were sent to molecular genetics confirmation of the diagnosis by whole exome sequencing with subsequent Sanger sequencing confirmation of the detected mutation in the proband and proband’s relatives. In members of the family with clinical features of CSNB1A the reading frame shift mutation was genetically confirmed in the NYX gene (c.283delC, p.His95fs, NM_022567.2). This mutation is inherited in X-linked form. This is the first report of a case with a novel and probable founder mutation from Russia associated with CSNB1A. Since the mRNA of a NYX gene consists of only 2696 base pairs, a gene replacement therapy, or CRISPR-based gene editing, or a similar approach may be envisaged for the correction of frameshift in His95fs position.

M.E. Ivanova1, D.S. Atarshchikov2, A.M. Demchinsky3, V.V. Strelnikov4, D. Barh5, G.V. Poryadin6, L.M. Balashova7, J.M. Salmasi6 1LLC “Oftalmic”, Moscow, Russian Federation 2Central Clinical Hospital under Presidential Affairs, Moscow, Russian Federation 3Autonomous nonprofit organization “Scientific and industrial laboratory “Sensor technology for deafblind”, Moscow, Russian Federation 4Research Centre for Medical Genetics, Moscow, Russian Federation 5Institute of Integrative Omics and Applied Biotechnology (IIOAB), Bangalore, India 6Pirogov Russian National Research Medical University, Moscow, Russian Federation 7Non-profit partnership International Scientific and Practical Center for the Proliferation of Tissues of Russia, Moscow, Russian Federation Background: Usher syndrome (USH) is a heterogeneous syndrome characterized by hearing loss and vision loss. The prevalence of USH is estimated to 5:100,000. USH is classified into three subtypes (I, II, and III) depending on the specific gene mutation, i.e., MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2 for type 1; USH2A, ADGRV1, DFNB31 for type 2; and CLRN1 for type 3. USH requires genetic studies to confirm the diagnosis, to manage patients, and to develop pathogenetically oriented treatment approaches. Historical aspects and development of molecular diagnosis of the disease, as well as evolution of approaches to the treatment are discussed. Aim: to study mutational spectrum in a cohort of Russian patients with USH and to analyze metabolome and interactome as well as pathogenic pathways of USH development to discover targeted therapies. Patients and Methods: 28 patients with USH were enrolled in the study and underwent examinations (clinical trial protocol No. NCT03319524 ). Comprehensive eye and ENT examination as well genetic studies were performed. The diagnosis was confirmed by MLPA next-generation sequencing and Sanger sequencing. Results: type 1 USH was diagnosed in 53.57% of patients and type 2 USH in 39.2% of patients. 17.85% were not confirmed genetically being in line with world statistics. Mutations in genes MYO7A (72.72%), CDH23 (9.09%), PCDH15 (9.09%), and USH1C (9.09%) were found in 11 patients. 11 mutations were identified in MYO7A gene, 54.54% were pathogenic mutations described for the first time. MYO7A: p.Q18* was the most common (27.27%) mutation associated with early and the most severe clinical manifestations. Two novel mutations (p.E1301* и c.158-?_318+?del) were identified in PCDH15 gene. In 90% of patients with type 2 USH, the diagnosis was confirmed genetically. 11 mutations were identified in USH2A gene, 27% were pathogenic causative mutations described for the first time. The most common mutations in USH2A were p.W3955* (50%), p.E767fs, p.R1653*, and c.8682–9A>G (20% each). Conclusion: detailed in silico analysis of metabolome and interactome as well as pathogenic pathways of USH development in Russian cohort was performed. The most promising treatment strategies including gene therapy are discussed. Keywords: USH, USH2A, MYO7A, mutation, Usher syndrome, congenital deaf-blindness, gene therapy, interactome, modeling. For citation: Ivanova M.E., Atarshchikov D.S., Demchinsky A.M. et al. The study of interactome in Russian patients with Usher syndrome to select priority approaches in pathogenetically oriented treatment. Russian Journal of Clinical Ophthalmology. 2019;19(4):180–188.

A case of enhanced S-cone syndrome misdiagnosed as idiopathic retinal vasculitis is presented. Etiology, pathogenesis and clinical features are described below.

Background: Usher syndrome (USH) is heterogeneous in nature and requires genetic test for diagnosis and management. Mutations in USH associated genes are reported in some populations except Russians. Here, we first time represented the mutation spectrum of a Russian USH cohort. Methods: Twenty-eight patients with USH were selected from 3214 patients from Deaf-Blind Support Foundation "Con-nection" during 2014-2016 following the observational study NCT03319524. Complete ophthalmologic, ENT, and vestibular medical tests were done for clinical characterization. NGS, MLPA, and Sanger sequencing were considered for genetic analysis. Results: Around 53.57% and 39.28% patients had USH1 and USH2, respectively; 17.85% cases (n = 5/28) had no known mutation. Eleven (73.33%) subjects showed variations in USH1 associated genes MYO7A (72.72%), CDH23 (9.09%), PCDH15 (9.09%), and USH1C (9.09%). Eleven mutations are detected in MYO7A where 54.54% are novel. MYO7A: p.Q18* was most frequent (27.27%) mutation and is associated with early manifestation and most severe clinical picture. Two novel mutations (p.E1301* and c.158-?_318+?del) are detected in PCDH15 gene. Around 90.90% patients suspected to be USH2 are confirmed by genetic testing. Eleven mutations detected in the USH2A gene, where 27.27% were novel. Most common USH2A mutation is p.W3955* (50%) followed by p.E767fs, p.R1653*, and c.8682-9A> G (20% each). Conclusion: The Russian USH cohort shows both novel and known USH mutations. Clinically the prevalence of USH2 is low (39.28%) and the frequency of MYO7A mutations responsible for USH1B is very high (63.63%, N = 7/11) compared to other cohorts. These seven patients carrying MYO7A mutations are preliminarily eligible for the UshStat (R) gene therapy.

There are two main approaches to visual function prosthesis in blindpatients with the use of brain-computer interfaces on the basisof either retinal or cortical stimulation by implanted electrodes. Themost complex in visual prosthesis is creation of the specific part ofthe interface that directly contacts with the tissues. In the paper discussed are questions of biocompatibility of microelectrode arraysand behavioral effects on animals (cats) for evaluating functionalityof the bioprosthetic device and its ability to induce phosphenes(visual sensations without light). Presented are new experimentalmethods and obtained results that allowed to determine phospheneinducing parameters of brain cortex electric stimulation in cats.Special attention is focused on description of the microelectrodearray properties necessary for safe application in humans during thelong time span, which is essential in cortical visual prosthesis.

ABCA4-associated mutation screening is extensively performed in European, African, American and several other populations for various retinopathies. However, it has not been well studied in a Russian cohort. Using next-generation (325 genes inherited disease panel) and Sanger sequencing technologies for the first time we documented the spectrum of genetic variations in a Russian retinopathy cohort of 51 patients from 10 ethnic groups. We found ABCA4 variations in 70.5% cases and one case with BEST1 variation. Multiple ABCA4 variations, ABCA4 + RDH12, and ABCA4 + BEST1 variations are also observed and the disease severity is found proportionate to the variation burden. Ten novel ABCA4 variations are detected of which 8 belongs to non-Slavonian population. Most of the detected known variations are found in European and American Stargardt disease populations. No retinopathy causing variation is detected in 14 (27%) cases suggesting that in this Russian retinopathies cohort the causal variants could be in genes that are not covered by our 325 gene panel. Therefore, whole genome/exome analysis is required to identify novel retinopathy associated genes and provide better disease management for this heterogeneous cohort.

Parameters of phosphene-evoking electrical stimulation of cat striatal cortex via electrodes of different types (surface and intracortical) were studied. Similar actions (paw raising) in response to the light pattern and to phosphene-inducing electric stimulation of the striatal cortex were demonstrated. It seems that the animals associated phosphene sensations with light patterns.