GENETICS OF SUSCEPTIBILITY TO INFECTIOUS DISEASES

Genetic characteristics of host organism may cause susceptibility to a variety of bacteria, viruses and fungi, as well as influence the course of infectious diseases. Multiple studies indicate the existence of alleles predisposing to infections. Furthermore, there are about 300 nosological entities of primary immunodeficiencies (PID), i.e., inherited defects of immunity. Timely diagnosis of such conditions is quite challenging; however, it is vital for improving quality of patient care. Modern methods of DNA analysis allow establishing genetic causes of vulnerability to certain infectious agents in many individual

ГЕНЕТИКА ПРЕДРАСПОЛОЖЕННОСТИ К ИНФЕКЦИОННЫМ ЗАБОЛЕВАНИЯМ

Genetic characteristics of host organism may cause susceptibility to a variety of bacteria, viruses and fungi, as well as influence the course of infectious diseases. Multiple studies indicate the existence of alleles predisposing to infections. Furthermore, there are about 300 nosological entities of primary immunodeficiencies (PID), i.e., inherited defects of immunity. Timely diagnosis of such conditions is quite challenging; however, it is vital for improving quality of patient care. Modern methods of DNA analysis allow establishing genetic causes of vulnerability to certain infectious agents in many individualsГенетические особенности организма играют важную роль в развитии инфекционных заболеваний, обусловливая восприимчивость к разнообразным бактериям, вирусам и грибам, а также оказывая влияние на течение болезни. Многочисленные исследования свидетельствуют о существовании аллелей предрасположенности к инфекциям. Кроме того, в настоящее время известно около 300 нозологических форм первичных иммунодефицитов (ПИД), которые представляют собой наследственные дефекты иммунитета. Своевременная диагностика таких состояний представляет значительные трудности, однако она крайне необходима для повышения качества лечения пациентов. Использование современных методов ДНК-анализа во многих случаях позволяет установить генетическую причину уязвимости по отношению к тем или иным инфекционным агентам.

Генетические варианты, выявленные у детей с рекуррентными инфекциями

Currently, the most effective way to diagnose hereditary defects of the immune system is molecular genetic research, the results of which are evaluated in conjunction with the data of clinical and laboratory studies.Aims of the sudy: to evaluate the frequency and spectrum of rare genetic variants associated with the development of primary immunodeficiency (PID) in children with recurrent infections.Materials and methods: DNA samples from 113 children with recurrent infections were analyzed by targeted multigene sequencing of 338 PID-associated genes. Results: Pathogenic variants appropriate to the potential diagnosis of PID were identified in 8% of patients. Interestingly, 47.8% of children had variants associated with auto-inflammatory disorders.В настоящее время наиболее эффективным способом диагностики наследственных дефектов иммунной системы является молекулярно-генетическое исследование, результаты которого оцениваются в совокупности с данными клинико-лабораторных исследований.Цель: оценка частоты и спектра редких вариантов генов, ассоциированных с развитием первичных иммунодефицитов (ПИД), у детей с рекуррентными инфекциями.Материалы и методы: Образцы ДНК 113 детей с рекуррентными инфекциями проанализированы методом таргетного высокопроизводительного секвенирования на предмет наличия мутаций в генах ПИД.Результаты: патогенные варианты, соответствующие потенциальному диагнозу ПИД, выявлены у 8% пациентов. У 47,8% детей выявлены варианты генов, ассоциированных с развитием аутовоспалительных заболеваний

Induction of neural crest stem cells from Bardet–Biedl syndrome patient derived hiPSCs

Neural crest cells arise in the embryo from the neural plate border and migrate throughout the body, giving rise to many different tissue types such as bones and cartilage of the face, smooth muscles, neurons, and melanocytes. While studied extensively in animal models, neural crest development and disease have been poorly described in humans due to the challenges in accessing embryonic tissues. In recent years, patient-derived human induced pluripotent stem cells (hiPSCs) have become easier to generate, and several streamlined protocols have enabled robust differentiation of hiPSCs to the neural crest lineage. Thus, a unique opportunity is offered for modeling neurocristopathies using patient specific stem cell lines. In this work, we make use of hiPSCs derived from patients affected by the Bardet–Biedl Syndrome (BBS) ciliopathy. BBS patients often exhibit subclinical craniofacial dysmorphisms that are likely to be associated with the neural crest-derived facial skeleton. We focus on hiPSCs carrying variants in the BBS10 gene, which encodes a protein forming part of a chaperonin-like complex associated with the cilium. Here, we establish a pipeline for profiling hiPSCs during differentiation toward the neural crest stem cell fate. This can be used to characterize the differentiation properties of the neural crest-like cells. Two different BBS10 mutant lines showed a reduction in expression of the characteristic neural crest gene expression profile. Further analysis of both BBS10 mutant lines highlighted the inability of these mutant lines to differentiate toward a neural crest fate, which was also characterized by a decreased WNT and BMP response. Altogether, our study suggests a requirement for wild-type BBS10 in human neural crest development. In the long term, approaches such as the one we describe will allow direct comparison of disease-specific cell lines. This will provide valuable insights into the relationships between genetic background and heterogeneity in cellular models. The possibility of integrating laboratory data with clinical phenotypes will move us toward precision medicine approaches

РОЛЬ ГЕНЕТИЧЕСКИХ ФАКТОРОВ В РАЗВИТИИ ГЕРПЕТИЧЕСКОГО ЭНЦЕФАЛИТА. СЛУЧАЙ ИЗ ПРАКТИКИ

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Genomic profiling of CHEK2*1100delC-mutated breast carcinomas

Background: CHEK2*1100delC is a moderate-risk breast cancer susceptibility allele with a high prevalence in the Netherlands. We performed copy number and gene expression profiling to investigate whether CHEK2*1100delC breast cancers harbor characteristic genomic aberrations, as seen for BRCA1 mutated breast cancers. Methods: We performed high-resolution SNP array and gene expression profiling of 120 familial breast carcinomas selected from a larger cohort of 155 familial breast tumors, including BRCA1, BRCA2, and CHEK2 mutant tumors. Gene expression analyses based on a mRNA immune signature was used to identify samples with relative low amounts of tumor infiltrating lymphocytes (TILs), which were previously found to disturb tumor copy number and LOH (loss of heterozygosity) profiling. We specifically compared the genomic and gene expression profiles of CHEK2*1100delC breast cancers (n = 14) with BRCAX (familial non-BRCA1/BRCA2/CHEK2*1100delC mutated) breast cancers (n = 34) of the luminal intrinsic subtypes for which both SNP-array and gene expression data is available. Results: High amounts of TILs were found in a relatively small number of luminal breast cancers as compared to breast cancers of the basal-like subtype. As expected, the

Спектр мутаций BRCA1/2 у пациенток армянского происхождения с раком молочной железы и яичника

The aim of the study was to compare the spectra of pathogenic BRCA1 and BRCA2 variants in patients with hereditary breast cancer (BC) and ovarian cancer (OC) from two groups of ethnic Armenians: Yerevan and cities of southern Russia.Material and Methods. 106 BC patients from the V.A. Fanardjian National Centre of Oncology (Yerevan, Republic of Armenia) and 117 BC and OC patients of Armenian origin who were referred to the Petrov National Medical Centre of Oncology (St. Petersburg, Russia) from several cancer centers of Russia (Krasnodar, Sochi, Pyatigorsk) were included into the study. The coding sequences of BRCA1 and BRCA2 genes were analyzed by the method of targeted high-throughput sequencing.Results. Pathogenic variants of BCRA1 and BCRA2 genes were detected in 16/106 (BRCA1: n=9, BRCA2: n=7; 15%) BC patients from Yerevan. The only recurrent mutation was the BRCA1 nonsense variant c.5444G>A [W1815X], accounting for 44% of all pathogenic alleles identified. In patients of Armenian origin from Russia, pathogenic BRCA1/2 variants were detected in 16/117 (14%) individuals (BRCA1: n=6, BRCA2: n=10). The proportion of samples with mutations was 13% in the group of BC patients and 19% in the group of OC patients. 75% of pathogenic alleles were represented by five recurrent mutations: BRCA1 c.2649_2650insGGCA, BRCA2 c.2808_2808_2811delACAA, BRCA1 c.4065_4068delTCAA, BRCA2 c.9027delT and BRCA2 c.8437G>T [G2813X]. The independent origin of the pathogenic BRCA2 c.2808_2808_2811delACAA variant in Armenian and non-Armenian patients was shown.Conclusion. A significant difference in the spectrum of BRCA1/2 mutations between Armenian patients from Yerevan and patients from southern regions of Russia was found. This should be taken into account when developing diagnostic programs.Цель исследования – сравнить спектры патогенных вариантов BRCA1 и BRCA2 у пациенток с наследственными формами рака молочной железы (РМЖ) и рака яичников (РЯ) – представительниц двух групп этнических армян: из Еревана и городов юга России.Материал и методы. В исследование включено 106 больных РМЖ из Национального центра онкологии им. В.А. Фанарджяна (Ереван, Республика Армения) и 117 пациенток с РМЖ и РЯ армянского происхождения, которые были направлены в НМИЦ онкологии им. Н.Н. Петрова (Санкт-Петербург) из нескольких онкологических диспансеров России (Краснодар, Сочи, Пятигорск). Анализ кодирующих последовательностей генов BRCA1 и BRCA2 выполнялся методом таргетного высокопроизводительного секвенирования.Результаты. В группе больных РМЖ из Еревана выявлено 16/106 (15 %) носительниц патогенных вариантов BRCA1/2 (BRCA1: n=9, BRCA2: n=7). Единственной повторяющейся мутацией оказался нонсенс-вариант BRCA1 c.5444G>A [W1815X], составляющий 44 % всех выявленных патогенных аллелей. У пациенток армянского происхождения из России патогенные варианты BRCA1/2 были обнаружены у 16/117 (14 %) человек (BRCA1: n=6, BRCA2: n=10). В группе пациенток с РМЖ доля образцов с мутациями составила 13 %, а у больных РЯ – 19 %. 75 % патогенных аллелей были представлены пятью повторяющимися мутациями: BRCA1 c.2649_2650insGGCA, BRCA2 c.2808_2811delACAA, BRCA1 c.4065_4068delTCAA, BRCA2 c.9027delT и BRCA2 c.8437G>T [G2813X]. Показано независимое происхождение патогенного варианта BRCA2 c.2808_2811delACAA у пациенток армянского и неармянского происхождения.Заключение. Спектр мутаций BRCA1/2 у пациенток армянского происхождения из Еревана и южных регионов России имеет существенные различия, что следует учитывать при разработке диагностических программ

Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent

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