| Description: |
Background. In cases of neurofibromatosis type 1 and type 2, pathogenic mutations are distributed evenly along the coding regions of the NF1 and NF2 genes. Herewith, in more than 50% of cases, the disease is the result of a de novo mutation. Therefore, the search for a causative mutation is particularly time-consuming and the catalogs of pathogenic and non-pathogenic genetic variants are an indispensable assistance handbook for geneticists in their work. Objective. To determine the spectrum of genetic alterations in Russian neurofibromatosis patients and to characterize novel pathogenic mutations and rare non-pathogenic genetic variants in the NF1 and NF2 genes. Material and methods. The study was carried out on the peripheral blood lymphocyte and/or tumor tissue DNA samples from 617 patients. NGS was performed on the Ion Torrent PGM and Ion Torrent S5 sequencing machines using NF1 and NF2 AmpliSeq gene panel. Gene panel encompasses exons of the NF1 and NF2 genes, adjacent intron segments (20-70 bp), 3’UTRs, and 5’UTRs. Sanger sequencing was used to verify pathogenic genetic variants and the MLPA method was used to search for NF1 and NF2 gross deletions. Result. Complex molecular genetic diagnostics of the NF1 and NF2 alterations was accomplished for 617 patients. The NF1 and NF2 mutations were detected in 303 and 19 cases, respectively. Conclusion. We have characterized 69 novel pathogenic mutations, 68 in the NF1 gene, and 1 in the NF2 gene, as well as 68 rare non-pathogenic genetic variants. Most non-pathogenic genetic variants are represented by synonymous SNPs and nucleotide substitutions in untranslated regions, which are particularly difficult to interpret during medical-genetic counseling. ; Актуальность. При нейрофиброматозе первого и второго типа патогенные мутации распределены вдоль кодирующих областей генов NF1 и NF2 равномерно, при этом более чем в 50% случаев заболевание является результатом мутации de novo . Как следствие, поиск патогенной мутации у пациента является особенно трудоемким, и ... |
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https://www.medgen-journal.ru/jour/article/view/599/380; Kresak JL, Walsh M. Hereditary Cancer Syndromes in Children: Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis. Journal of pediatric genetics. 2016 Jun;5(2):98.; Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1 (NF1). Journal of medical genetics. 2006(14):81-88.; Friedman JM. Epidemiology of neurofibromatosis type 1. American journal of medical genetics. 1999 Mar 26;89(1):1-6.; Шнайдер НА. Нейрофиброматоз 1-го типа: этиопатогенез, клиника, диагностика, прогноз. Международный неврологический журнал. 2007(5):162-7.; Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using US death certificates. The American Journal of Human Genetics. 2001 May 1;68(5):1110-8.; Xu G, O’Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R, Weiss R. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990 Aug 10;62(3):599-608.; Cichowski K, Jacks T. NF1 tumor suppressor gene function: narrowing the GAP. Cell. 2001 Feb 23;104(4):593-604.; Barton B, North K. Social skills of children with neurofibromatosis type 1. Developmental Medicine & Child Neurology. 2004;46(8):553-563.; Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR. Neurofibromatosis type 2. The Lancet. 2009 Jun 6;373(9679):1974-86.; Thomas G. Merel P., Sanson M. et al. Neurofibromatosis type 2. European Journal of Cancer. 1994;30(13):1981-1987.; Evans G. R., Lloyd S. K. W., Ramsden R. T. Neurofibromatosis type 2. Medical Genetics in the Clinical Practice of ORL. Karger Publishers. 2011(70):91-98.; McClatchey AI, Giovannini M. Membrane organization and tumorigenesis - the NF2 tumor suppressor, Merlin. Genes & development. 2005 Oct 1;19(19):2265-77.; Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes & development. 2003 May 1;17(9):1090-100.; Alkindy A, Chuzhanova N, Kini U, Cooper DN, Upadhyaya M. Genotype-phenotype associations in neurofibromatosis type 1 (NF1): an increased risk of tumor complications in patients with NF1 splice-site mutations? Human genomics. 2012 Dec;6(1):12.; Чаплыгина МС, Кузнецова ЕБ, Танас АC и др. Результаты использования новой медицинской технологии комплексной ДНК-диагностики нейрофиброматоза. Медицинская генетика. 2016;15(11):24-8.; Рыжкова О.П., Кардымон О.Л., Прохорчук Е.Б., Коновалов Ф.А., Масленников А.Б., Степанов В.А., Афанасьев А.А., Заклязьминская Е.В., Костарева А.А., Павлов А.Е., Голубенко М.В., Поляков А.В., Куцев С.И. Руководство по интерпретации данных, полученных методами массового параллельного секвенирования (MPS). Медицинская генетика. 2017;16(7):4-17. |
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