Inter- and intrafamilial diversity based on genotype and phenotype correlations of Osteogenesis Imperfecta
Date
2019-09-16
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Abstract
Osteogenesis Imperfecta (OI) on haruldane geneetiline haigus, mis on tuntud ka kui “habraste luude haigus”. Patsientide fenotüübid varieeruvad kergest osteopeeniast kuni raskete või isegi letaalsete juhtudeni. Umbes 90% juhtumitest on haiguse peamiseks sihtmärgiks I tüüpi kollageen.
Käesoleva doktoritöö eesmärgiks oli tuvastada genotüüpide-fenotüüpide korrelatsioone OI perekondades perekonnasisese ja -vahelise varieeruvusega. Me uurisime OI patsientide kliinilisi tunnused ja kollageeni patogensete variantide spektrit. Analüüsisime de novo kollageeni-OI juhtumeid ja genotüübi-fenotüübi korrelatsioone Eesti, Ukraina ja Vietnami OI patsientidel. Lisaks viisime läbi mittekollageeni-OI patsientide geneetilise sõeluuringu harvaesineva OI vormi (tüüp V) tuvastamiseks. Lõppeesmärgi saavutamiseks analüüsisime perekondade siseseid ja perekondade vahelisi varieeruvusi kollageeni patogensete variantidega OI perekondades.
Eestis tuvastasime 90%-l OI patsientidest I tüüpi kollageeni patogensed variantid. Enamus neist põhjustasid kollageeni kvantitatiivse defekti. Ukraina OI patsientidest 64% kandsid I tüüpi kollageeni patogense variandi ja nende hulgas oli kvalitatiivsete ja kvantitatiivsete kollageeni defektide arv peaaegu võrdne. Pooled tuvastatud OI patogensetest variantidest olid varem kirjanduses kirjeldamata. Samuti ei olnud 57%-l patsientidel varasemat OI esinemist perekonnas teada ja haigus ilmnes de novo. Tuvastasime viis perekonda, kellel esineb tüüpi V OI, kuid esinesid varieeruvad fenotüübid, mis mitmel juhul sarnanesid klassikalise kollageen-OI fenotüüpidega. Perekondade sisene ja vaheline varieeruvus korreleerus kollageeni defekti tüübi ja geeniga. Kvalitatiivse kollageeni defektiga patsientidel oli suurem fenotüübiline varieeruvus võrreldes nendega, kellel esines kvantitatiivne kollageeni defekt.
Doktoritöö tulemused laiendavad arusaamist Osteogenesis Imperfecta geneetikast, etioloogiast, patogeneesist ja “haprade luude” fenotüübi seostest. Käesolev uuring aitab kaasa OI diagnoosimisele ja edasistele OI-uuringutele, mille eesmärk on parandada OI patsientide elukvaliteeti.
Osteogenesis Imperfecta (OI) is a rare genetic disorder, also known as a “brittle bone disease”. Patients’ phenotypes range from mild bone fragility to severe or even lethal cases. In up to 90% of cases the main target of the disorder is collagen type I. Current thesis aimed to identify genotype-phenotype associations in OI families with inter- and intrafamilial phenotypical variability. We have investigated clinical characteristics and described spectrum of collagen-related pathogenic variants in OI patients. We have analyzed de novo cases among collagen-related OI patients and genotype-phenotype correlations in OI patients of Estonian, Ukrainian and Vietnamese origin. Further, we have performed genetic screening of non-collagen OI patients for a rare OI form - type V. Finally, inter- and intrafamilial diversity in collagen-related OI families was analyzed. In Estonian population 90% of patients harbored collagen pathogenic variants. Out of them, majority had quantitative defect of the collagen I. Among Ukrainian OI patients, 64% had collagen I pathogenic variants, with almost equal amount of qualitative and quantitative collagen defects among them. Almost half of all identified OI pathogenic variants were undescribed previously. 57% of patients did not have OI family history and the disorder appeared as de novo. We have identified five families with OI type V with variable phenotypes, which mimicked classical collagenous OI types. Identified inter- and intrafamilial variability correlated with type of the collagen defect and affected gene. So that, patients who had qualitative collagen defect had higher phenotype variability compared to those who suffered from quantitative collagen defect. Results of current thesis broaden understanding of Osteogenesis Imperfecta genetics, etiology, pathogenesis and development of a “brittle bone” phenotype. Current work contributes into OI diagnosis, family planning and further OI research with aim to improve quality of life for OI patients.
Osteogenesis Imperfecta (OI) is a rare genetic disorder, also known as a “brittle bone disease”. Patients’ phenotypes range from mild bone fragility to severe or even lethal cases. In up to 90% of cases the main target of the disorder is collagen type I. Current thesis aimed to identify genotype-phenotype associations in OI families with inter- and intrafamilial phenotypical variability. We have investigated clinical characteristics and described spectrum of collagen-related pathogenic variants in OI patients. We have analyzed de novo cases among collagen-related OI patients and genotype-phenotype correlations in OI patients of Estonian, Ukrainian and Vietnamese origin. Further, we have performed genetic screening of non-collagen OI patients for a rare OI form - type V. Finally, inter- and intrafamilial diversity in collagen-related OI families was analyzed. In Estonian population 90% of patients harbored collagen pathogenic variants. Out of them, majority had quantitative defect of the collagen I. Among Ukrainian OI patients, 64% had collagen I pathogenic variants, with almost equal amount of qualitative and quantitative collagen defects among them. Almost half of all identified OI pathogenic variants were undescribed previously. 57% of patients did not have OI family history and the disorder appeared as de novo. We have identified five families with OI type V with variable phenotypes, which mimicked classical collagenous OI types. Identified inter- and intrafamilial variability correlated with type of the collagen defect and affected gene. So that, patients who had qualitative collagen defect had higher phenotype variability compared to those who suffered from quantitative collagen defect. Results of current thesis broaden understanding of Osteogenesis Imperfecta genetics, etiology, pathogenesis and development of a “brittle bone” phenotype. Current work contributes into OI diagnosis, family planning and further OI research with aim to improve quality of life for OI patients.
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Keywords
geneetilised haigused, ebatäiuslik luuteke, kollageen tüüp 1, geneetiline muutlikkus, fenotüübiline muutlikkus, Eesti, Ukraina, Vietnam