Микроструктурни геномни аберации при пациенти с вродени малформации
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Дата
2014-07-07
Автори
Хаджидекова/Hadjidekova, Савина Петрова/Savina Petrova
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Издател
Резюме
Цел и задачи *****
* Цел ***
Целта на настоящата дисертация e чрез молекулно кариотипиране да се разкрият микроструктурни геномни изменения при пациенти с идиопатични вродени малформации, да се установи произхода на патологичните вариации и да се анализират фенотип/генотипните корелации.
* Задачи ***
1. Да се разкрият типа и честотата на патологичните микроструктурни геномни изменения като фактори в етиологията на вродените малформации;
2. Да се определят честотата и типа на нормалните вариации и на вариантите с неясно клинично значение при вродените малформации;
3. Да се установят фенотип/генотипни корелации при патологични микроаберации и да се потърсят кандидат-гени за патологичните нарушения;
4. Да се оптимизира технологията на микрочиповата СГХ с оглед въвеждането й като метод за рутинна генетична диагностика на вродените малформации;
5. Да се сравнят възможностите за диагностика на две различни микрочипови платформи - ВАС-чипове срещу олиго-микрочипове;
6. Да се определи генетичния риск при засегнати семейства с микроделеционни/микродупликационни синдроми, за да се подобри генетичното консултиране;
7. Да се създаде ДНК банка от деца с вродени малформации и родителите им за бъдещи геномни изследвания. ******************************** Microstructural genomic imbalances in patients with congenital malformations The problem of congenital malformations is a particularly topical issue, given the high frequency of congenital defects of development (3-5%), their high average share (33%) in neonatal infant mortality, the significant etiological heterogeneity and their difficult diagnosis. Approximately in 40% of the cases the aetiology remains unclear. It is believed that many of these cases are due to yet unidentified genetic defects. The inclusion of new methodological approaches holds promise for better understanding of this congenital abnormality group in the post genomic era. One of the most modern methods for screening unbalanced quantitative changes in the genome is the microarray comparative genomic hybridization (array CGH). This technology has proven its high sensitivity in identifying candidate genes for many human tumors. The recent years trend is to use this technology for the detection of candidate genes for human diseases of unknown etiology.
In the current study, the preliminary group included 98 children of both sexes, selected in a genetic clinic after a rigorous sampling was performed to exclude recognized etiological development defects. In our genetic study of patients with congenital malformations a combination of methods was applied - cytogenetic analysis, molecular cytogenetic analysis by FISH method, DNA microarrays analysis of oligonucleotides and BAC - arrays.
After cytogenetic analysis in 11 patients from the preliminary group chromosomal disorders were found. In 6 patients microdeletion syndrome was proved with FISH analysis. 52 patients out of the remaining 81 patients were selected for array CGH analysis after implementing stringent criteria (a combination of congenital malformations, dysmorphic features and behavioral disorders, and patients with multiple abnormalities and the presence of at least one major anomaly). Six patients were examined consecutively with BAC - and oligo - microarrays to compare the diagnostic capabilities of both platforms.
The results of analysis of microarrays revealed definite etiology in 9 out of 52 patients tested. 15 pathological aberrations were found in them. All pathological findings were validated by FISH analysis. Different genotype / phenotypic correlations between different patients were confirmed. In addition, the majority of the patients tested (41 patients) showed normal variations in the number of copies and variations of unknown clinical significance (34 patients). Analyses of the type and distribution of the different variations was performed and the clinical significance of variants of unknown nature was discussed.
Molecular kariotyping is coming up as an extremely suitable method for genetic diagnosis of patients with unclear dismorphic syndromes and intellectual
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disability. It could successfully replace the cytogenetic study and be applied as a first method of choice.
Future development. Our results show the advantages of high resolution microarrays for clinical diagnosis of patients with intellectual disability and congenital malformations, but also highlight the need for extensive population studies revealing the molecular nature and clinical significance of different CNVs and the creation of detailed maps of variations in the Bulgarian population. This would facilitate greatly the precise interpretation of specific genomic imbalances in clinical aspect and would ease the widespread introduction of microarrays in diagnostic practice not only for postnatal diagnosis of individuals with developmental delay and dysmorphism, but also for prenatal genetic diagnosis.
Описание
Дисертация за присъждане на образователна и научна степен "Доктор" /CD/ / Савина Петрова Хаджидекова . - София, 2011 . - 234 с. + Автореферат /CD/. Област на висше образование: „Здравеопазване и спорт”, Шифър 7.1.
Професионално направление: „Медицина”
Научна специалност: „Генетика”, (шифър 01.06.06)
НАУЧЕН РЪКОВОДИТЕЛ: ПРОФ. Д-Р ДРАГА ТОНЧЕВА, ДБН.
НАУЧНО ЖУРИ В СЪСТАВ:
ПРЕДСЕДАТЕЛ: Доц. д-р Радка Стефанова Тинчева, дмн - становище;
ЧЛЕНОВЕ: 1. Проф. д-р Спаска Димитрова Петкова, дбн- рецензент;
2. Проф. д-р Бойка Борисова Аначкова, дбн - рецензент;
3. Член кор. проф. д-р Иван Георгиев Иванов, дбн - становище;
4. Проф. д-р Драга Иванова Тончева, дбн – становище.
Ключови думи
Генетични заболявания, Хромозомни аберации, Генетика, медицинска - дисертации, Хромозомни аномалии - дисертации, Аномалии - дисертации , Genetic Diseases, Inborn - dissertations, Genetics, Medical - dissertations, Chromosome Aberrations - dissertations