Marianna E Ivanova1, Vladimir N Trubilin2, Dmitry S Atarshchikov3, Andrey M Demchinsky4, Vladimir V Strelnikov5, Alexander S Tanas5, Olga M Orlova2, Anton S Machalov6, Kira V Overchenko6, Tatiana V Markova5, Daria M Golenkova2, Kirill I Anoshkin5, Ilya V Volodin5, Dmitry V Zaletaev7, Andrey A Pulin8, Irina I Nadelyaeva9, Alexey I Kalinkin5,7, Debmalya Barh10,11. 1. a Oftalmic LLC , Moscow , Russia. 2. b Center of Ophthalmology , Federal Medical-Biological Agency State Research Center , Burnasyan, Moscow , Russia. 3. c Central Clinical Hospital under President Affairs , Moscow , Russia. 4. d Sensor-Tech Scientific and Industrial Laboratory , Moscow , Russia. 5. e Federal State Budgetary Institution , Research Centre for Medical Genetics , Moscow , Russia. 6. f Surdology and Otoneurology Departments , Scientific and Clinical Center for Otorhinolaryngology of FMBA of Russia , Moscow , Russia. 7. g Laboratory of Medical Genetics, Institute of Molecular Medicine , I. M. Sechenov First Moscow State Medical University , Moscow , Russia. 8. h Laboratory of Cell Biology and Developmental Pathology , Federal State Budgetary Scientific Institution "Institute of General Pathology and Pathophysiology" , Moscow , Russia. 9. i Federal State Budget Institution of Higher Education , A.I. Yevdokimov Moscow State University of Medicine and Dentistry, The Ministry of Health Care of the Russia. 10. j Center for Genomics and Applied Gene Technology , Institute of Integrative Omics and Applied Biotechnology (IIOAB) , Nonakuri, Purba Medinipur , West Bengal , India. 11. k Division of Bioinformatics and Computational Genomics , NITTE University Center for Science Education and Research (NUCSER), NITTE (Deemed to be University) , Mangaluru , Karnataka , India.
Abstract
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® gene therapy.
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® gene therapy.
Authors: Andrej Zupan; Ana Fakin; Saba Battelino; Martina Jarc-Vidmar; Marko Hawlina; Crystel Bonnet; Christine Petit; Damjan Glavač Journal: Genes (Basel) Date: 2019-12-05 Impact factor: 4.096