MÖGLICHKEITEN UND GRENZEN DER GENDIAGNOSTIK

Forschungsgegenstand der Humangenetik ist die genetisch bedingte Variabilität zwischen den Menschen. Die klinische Genetik als medizinisches Anwendungsgebiet der Humangenetik beschäftigt sich mit den genetischen Grundlagen von Erkrankungen. Erblich bedingte Erkrankungen sind häufiger als meistens angenommen. Ungefähr 5 % aller Neugeborenen weisen genetisch bedingte Erkrankungen oder Fehlbildungen auf. Viele genetisch bedingte Erkrankungen werden allerdings erst im Laufe des Lebens manifest. Unter Berücksichtigung dieser spät manifestierenden Erkrankungen dürften ca. zwei Drittel aller Menschen im Laufe ihres Lebens von einer oder mehreren erblich (mit)bedingten Erkrankungen betroffen sein. Auch wenn die klinische Genetik zu den jüngsten medizinischen Disziplinen gehört, sind Beobachtungen über erbliche Zusammenhänge und Versuche, Konsequenzen daraus abzuleiten, recht alt. Zum Beispiel wird im babylonischen Talmud erwähnt, daß man von der Beschneidung eines Knaben absehen sollte, wenn bei einem Bruder oder Onkel mütterlicherseits schwere Blutungen im Rahmen dieses Eingriffs aufgetreten sind. Hinter dieser „genetischen Beratung“ steckt die Beobachtung, daß Frauen Überträgerinnen der Hämophilie sein können, von der aufgrund des X-chromosomal-rezessiven Erbgangs männliche Personen mehrfach in einer Familie betroffen sein können. Die Erkenntnis formalgenetischer Aspekte beim Menschen nach der Wiederentdeckung der Mendelschen Regeln im letzten Jahrhundert hat erstmals wissenschaftlich begründete Aussagen zur Wahrscheinlichkeit für das Auftreten erblich bedingter Erkrankungen erlaubt. Die Fortschritte der Humangenetik, vor allem der molekularen Humangenetik, machen es zunehmend möglich, aus solchen Wahrscheinlichkeiten Gewißheiten zu machen. Damit werden einerseits Hoffnungen geknüpft, daß Erkrankungen immer sicherer diagnostiziert werden und sich in wachsendem Maße therapeutische Konsequenzen daraus ableiten lassen. Andererseits ruft die Vorstellung, daß immer mehr erbliche Merkmale identifizierbar und voraussehbar werden, bei den meisten Unbehagen hervor. In diesem Zusammenhang sollen Möglichkeiten, Grenzen und einige ethische Aspekte der gegenwärtigen Gendiagnostik diskutiert werden

Summaries

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Further evidence that imbalance of WT1 isoforms may be involved in Denys-Drash syndrome

No abstract availabl

Исследование алгоритмов функционирования СМО с использованием библиотеки SimEvents

Выпускная квалификационная работа 80 с., 18 рис., 6 табл., 21 источник. Объект исследования — модель управления графитовыми стержнями в ядерном реакторе. Цель работы — разработка модели управления замедляющими стержнями в реакторе с использованием библиотеки SimEvents. Изучены принципы имитационного моделирования с помощью библиотек SimEvents, Simulink. Разработана модель управления графитовыми стержнями в реакторе, получены параметры системы, проведен их анализ. Модель может использоваться как имитатор физического процесса в атомном производстве. Имитационная модель дает подтверждение расчетов, прогноз работы системы, позволяет исследовать работу в критических режимах. Планируется изучение новых характеристик системы, разработка более сложной модели, параметров, влияющих на новую модельGraduation qualification project consist of 80 p., 18 fig., 6 tab., 21 sources. The object of this study is graphite rods’s control model in nuclear reactors. The purpose of work – graphite rods’s control model development using SimEvents in nuclear reactors. Is studied the simulation principles using libraries SimEvents, Simulink. Are obtained the model of the control rods in the reactor graphite, the system parameters , their analysis was carried out. The model can be used as a simulator of a physical process in nuclear industry. A simulation model provides evidence calculations, the forecast of the system, allows you to explore the critical operation. It is planned to study the characteristics of the new system, the development of a more complex model, the parameters affecting a mode

Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) affects similar to 1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of > 60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.Peer reviewe

Технология и техника сооружения поисково-оценочных скважин на Майском месторождении алмазов (Республика Саха (Якутия))

Объектом исследования является кимберлитовая руда на объекте "Майское". Цель работы: составление проекта на бурение поисково-оценочных скважин; геологическое изучение объекта; разработка технологии проведе-ния поисковых работ на участке; разработка управления и организации работ на объекте. В процессе проектирования проводились: выбор бурового оборудования; поверочный расчет выбранного оборудования; расчет режимных параметров; анализ вредных и опасных факторов при проведении геологоразведочных работ и меры по их предупреждению; выбор вспомогательного оборудования и организации работ; сметно-финансовый расчет.The object of the study is kimberlite ore at the Mayskoye facility. The purpose of the work: preparation of the project for the drilling of exploration and evaluation wells; geological study of the object; development of technology for prospecting works on the site; development of management and organization of works on the site. In the process of design were carried out: selection of drilling equipment; calibration calculation of the selected equipment; calculation of operating parameters; analysis of harmful and dangerous factors during exploration and measures to prevent them; selection of auxiliary equipment and organization of wo

Novel associations in disorders of sex development: findings from the I-DSD registry

Context: The focus of care in disorders of sex development (DSD) is often directed to issues related to sex and gender development. In addition, the molecular etiology remains unclear in the majority of cases.<p></p> Objective: To report the range of associated conditions identified in the international DSD (I-DSD) Registry.<p></p> Design, Setting, and Patients: Anonymized data were extracted from the I-DSD Registry for diagnosis, karyotype, sex of rearing, genetic investigations, and associated anomalies. If necessary, clarification was sought from the reporting clinician.<p></p> Results: Of 649 accessible cases, associated conditions occurred in 168 (26%); 103 (61%) cases had one condition, 31 (18%) had two conditions, 20 (12%) had three conditions, and 14 (8%) had four or more conditions. Karyotypes with most frequently reported associations included 45,X with 6 of 8 affected cases (75%), 45,X/46,XY with 19 of 42 cases (45%), 46,XY with 112 of 460 cases (24%), and 46,XX with 27 of 121 cases (22%). In the 112 cases of 46,XY DSD, the commonest conditions included small for gestational age in 26 (23%), cardiac anomalies in 22 (20%), and central nervous system disorders in 22 (20%), whereas in the 27 cases of 46,XX DSD, skeletal and renal anomalies were commonest at 12 (44%) and 8 (30%), respectively. Of 170 cases of suspected androgen insensitivity syndrome, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations.<p></p> Conclusions: Over a quarter of the cases in the I-DSD Registry have an additional condition. These associations can direct investigators toward novel genetic etiology and also highlight the need for more holistic care of the affected person.<p></p&gt

Novel associations in disorders of sex development: findings from the I-DSD registry

Context: The focus of care in disorders of sex development (DSD) is often directed to issues related to sex and gender development. In addition, the molecular etiology remains unclear in the majority of cases.<p></p> Objective: To report the range of associated conditions identified in the international DSD (I-DSD) Registry.<p></p> Design, Setting, and Patients: Anonymized data were extracted from the I-DSD Registry for diagnosis, karyotype, sex of rearing, genetic investigations, and associated anomalies. If necessary, clarification was sought from the reporting clinician.<p></p> Results: Of 649 accessible cases, associated conditions occurred in 168 (26%); 103 (61%) cases had one condition, 31 (18%) had two conditions, 20 (12%) had three conditions, and 14 (8%) had four or more conditions. Karyotypes with most frequently reported associations included 45,X with 6 of 8 affected cases (75%), 45,X/46,XY with 19 of 42 cases (45%), 46,XY with 112 of 460 cases (24%), and 46,XX with 27 of 121 cases (22%). In the 112 cases of 46,XY DSD, the commonest conditions included small for gestational age in 26 (23%), cardiac anomalies in 22 (20%), and central nervous system disorders in 22 (20%), whereas in the 27 cases of 46,XX DSD, skeletal and renal anomalies were commonest at 12 (44%) and 8 (30%), respectively. Of 170 cases of suspected androgen insensitivity syndrome, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations.<p></p> Conclusions: Over a quarter of the cases in the I-DSD Registry have an additional condition. These associations can direct investigators toward novel genetic etiology and also highlight the need for more holistic care of the affected person.<p></p&gt

Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation

The impact of CFNS-causing EFNB1 mutations on ephrin-B1 function

BACKGROUND: Mutations of EFNB1 cause the X-linked malformation syndrome craniofrontonasal syndrome (CFNS). CFNS is characterized by an unusual phenotypic pattern of inheritance, because it affects heterozygous females more severely than hemizygous males. This sex-dependent inheritance has been explained by random X-inactivation in heterozygous females and the consequences of cellular interference of wild type and mutant EFNB1-expressing cell populations. EFNB1 encodes the transmembrane protein ephrin-B1, that forms bi-directional signalling complexes with Eph receptor tyrosine kinases expressed on complementary cells. Here, we studied the effects of patient-derived EFNB1 mutations predicted to give rise to truncated ephrin-B1 protein or to disturb Eph/ephrin-B1 reverse ephrin-B1 signalling. Five mutations are investigated in this work: nonsense mutation c.196C > T/p.R66X, frameshift mutation c.614_615delCT, splice-site mutation c.406 + 2T > C and two missense mutations p.P54L and p.T111I. Both missense mutations are located in the extracellular ephrin domain involved in Eph-ephrin-B1 recognition and higher order complex formation. METHODS: Nonsense mutation c.196C > T/p.R66X, frameshift mutation c.614_615delCT and splice-site mutation c.406+2T > C were detected in the primary patient fibroblasts by direct sequencing of the DNA and were further analysed by RT-PCR and Western blot analyses.The impact of missense mutations p.P54L and p.T111I on cell behaviour and reverse ephrin-B1 cell signalling was analysed in a cell culture model using NIH 3T3 fibroblasts. These cells were transfected with the constructs generated by in vitro site-directed mutagenesis. Investigation of missense mutations was performed using the Western blot analysis and time-lapse microscopy. RESULTS AND DISCUSSION: Nonsense mutation c.196C > T/p.R66X and frameshift mutation c.614_615delCT escape nonsense-mediated RNA decay (NMD), splice-site mutation c.406+2T > C results in either retention of intron 2 or activation of a cryptic splice site in exon 2. However, c.614_615delCT and c.406+2T > C mutations were found to be not compatible with production of a soluble ephrin-B1 protein. Protein expression of the p.R66X mutation was predicted unlikely but has not been investigated.Ectopic expression of p.P54L ephrin-B1 resists Eph-receptor mediated cell cluster formation in tissue culture and intracellular ephrin-B1 Tyr324 and Tyr329 phosphorylation. Cells expressing p.T111I protein show similar responses as wild type expressing cells, however, phosphorylation of Tyr324 and Tyr329 is reduced. CONCLUSIONS: Pathogenic mechanisms in CFNS manifestation include impaired ephrin-B1 signalling combined with cellular interference