20.500.12556/RUL-174139 Genetski vzroki prirojenih srčnih napak Genetic etiology of congenital heart disease Prirojene srčne napake (PSN) predstavljajo najpogostejšo prirojeno razvojno nepravilnost. Prisotne so pri okoli 1 % otrok in so pomemben vzrok neonatalne umrljivosti, obolevnosti in dolgoročne invalidnosti ter zato predstavljajo pomemben javnozdravstveni izziv, obenem pa so v kar 50 do 70 % etiološko nepojasnjene. Diagnostični izplen omejujeta tako klinična heterogenost kot tudi genetska heterogenost. V doktorski nalogi smo opredelili genetsko etiologijo PSN na reprezentativni kohorti bolnikov, s sočasno uporabo molekularne kariotipizacije in NGS pri bolnikih z izoliranimi in sindromskimi PSN. Raziskava je vključevala 609 bolnikov, ki so bili obravnavani na KIGM UKC Ljubljana med januarjem 2011 in decembrom 2024. Fenotipske podatke smo pridobili s sistematičnim retrospektivnim pregledom medicinske dokumentacije. Celokupno smo genetski vzrok opredelili pri 20,2 % bolnikov s PSN, pri 28,3 % bolnikov s sindromsko klinično sliko PSN in 9 % bolnikov z izolirano PSN. Opredelili smo 65 različnih genetskih vzrokov za PSN, ki so vključevali 29 znanih mikrodelecijskih/mikroduplikacijskih sindromov in 36 različnih monogenskih vzrokov. Dodatno smo med monogenskimi genetskimi vzroki odkrili sedem novih vzročnih različic v šestih genih, prvič opisanih pri naših bolnikih. Z izsledki doktorske naloge smo prikazali pomen postavljene genetske diagnoze tudi v skupini bolnikov z izoliranimi PSN, kjer je postavljena genetska diagnoza lahko zelo pomembna pri načrtovanju zdravljenja in sledenja, še posebej v okviru neonatalne obravnave. Z integracijo mednarodnih kliničnih genetskih panelov, orodja Exomiser, analize genov, pomembnih za embrionalni razvoj srca, in genov, identificiranih s pristopom GWAS, smo identificirali 15 novih kandidatnih genov (USP15, USP34, MYOM2, FBLN2, XAB2, CTBP2, CMYA5, JMJD1C, SPTBN5, FLRT2, RXRA, TAGLN, MYH7B, TFDP2, TOX2), ki lahko prispevajo k razumevanju molekularne patologije PSN. Z analizo PPI med kandidatnimi geni in geni, ki so že bili vzročno povezani s PSN, smo z več različnimi aplikacijami (STRING, cytoHubba, Metascape in g:Profiler) znotraj programa Cytoscape ocenjevali verjetnost, da so kandidatni geni vpleteni v nastanek PSN. Glede na pridobljene rezultate analize in na podatke, dostopne v že objavljeni literaturi, sta najboljša kandidatna gena RXRA in USP15. Congenital heart defects (CHDs) represent the most prevalent congenital developmental anomaly, affecting approximately 1% of children. They are a leading cause of neonatal mortality, morbidity, and long-term disability, and thus pose a significant public health challenge. The etiology of CHDs remains unexplained in 50 to 70% of cases, with diagnostic yield limited by both clinical and genetic heterogeneity. This doctoral thesis aims to clarify the genetic etiology of CHDs in a representative patient cohort. A concurrent diagnostic strategy was employed, utilizing both molecular karyotyping and next-generation sequencing (NGS) in individuals with isolated and syndromic CHDs. The study included 609 patients who underwent genetic diagnostics at the Department of Medical Genetics, University Medical Centre Ljubljana, between January 2013 and December 2024. Phenotypic data were systematically characterized through retrospective review of medical records. A genetic cause was identified in 20.2% of all CHD patients, with a diagnostic yield of 28.3% in syndromic cases and 9% in isolated cases. In total, 65 distinct genetic causes were identified, including 29 known microdeletion or microduplication syndromes and 36 monogenic causes. Among the monogenic causes, seven novel causal variants in six genes were discovered in this population. Establishing a genetic diagnosis in patients with isolated CHDs provides substantial clinical benefits by informing treatment plans and optimizing long-term follow-up, particularly in neonatal care. The study integrated internationally validated clinical genetic panels, the Exomiser tool, analysis of genes essential for embryonic heart development, and GWAS-associated genes. This approach led to the identification of 15 novel candidate genes (USP15, USP34, MYOM2, FBLN2, XAB2, CTBP2, CMYA5, JMJD1C, SPTBN5, FLRT2, RXRA, TAGLN, MYH7B, TFDP2, TOX2) that may contribute to the molecular pathology of CHDs. To evaluate the involvement of these candidate genes in CHD development, a protein-protein interaction analysis was performed between candidate genes and those with established etiological links to CHD. Bioinformatic analyses were conducted using the Cytoscape platform and integrated applications including STRING, cytoHubba, Metascape, and g:Profiler. Based on the integrated analysis and supporting literature, RXRA and USP15 are proposed as the most promising candidate genes potentially implicated in CHD pathogenesis. prirojene srčne napake mikrodelecije mikroduplikacije točkovne mutacije sekvenciranje naslednje generacije eksomsko sekvenciranje molekularna kariotipizacija kardiogeneza GWAS congenital heart disease microdeletions microduplications single nucleotide variants next-generation sequencing exome sequencing chromosomal microarrays cardiogenesis GWAS true false false Slovenski jezik Angleški jezik Doktorsko delo/naloga 2025-09-28 07:15:14 2025-09-28 07:15:37 2025-11-18 03:55:21 0000-00-00 00:00:00 2025 0 0 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 36251 251366147 8122.pdf 8122.pdf 1 1D5F4A57DCD96C1C56389A7A8ACB98A7 62bcdaea1636864491ee9ab4bd19139e9d3a78c34c11f45b72fb1744e5b4d5ca 019db917-9c2a-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=218899 Biotehniška fakulteta 0 0 0