{"id":{"repo_id":"u-iceland","oai_identifier":"oai:skemman.is:1946/50267"},"canonical_url":"https://search.dev.ndltd.org/etd/u-iceland/oai:skemman.is:1946/50267","repository":{"repo_id":"u-iceland","name":"University of Iceland","base_url":"https://skemman.is/oai/request"},"display":{"title":"Isoform-Specific Variant and Expression Analysis of Epigenetic Genes in Neurodevelopment and Disease","abstract":"Isoform-Specific Genetic Analysis of Epigenetic Machinery Genes in Neurodevelopment and Disease Úlfur Benedikt Fjölnisson¹, Katrín Möller¹, Hans Tómas Björnsson¹,²,³ ¹ Department of Medicine, University of Iceland, Reykjavík, Iceland ² Johns Hopkins University, Baltimore, USA ³ University Hospital, Reykjavík, Iceland Introduction Missense mutations in epigenetic machinery (EM) genes are frequently associated with neurodevelopmental disorders. Studying the isoform-specific distribution of pathogenic variants and the timing of isoform expression may reveal critical mechanisms underlying these diseases. Aims To assess whether pathogenic missense variants are enriched in regions unique to non-canonical isoforms and whether these isoforms show stage-specific expression during neurodevelopment. Methods Public databases (ClinVar, gnomAD, Ensembl BioMart) were used to compute missense variant densities in non-overlapping, isoform-specific exons of EM genes. Genome-wide variant data were used to ensure sufficient coverage. Enrichment was tested using Fisher’s exact test with FDR correction. Isoform expression patterns across stages of mouse neurodevelopment were analyzed using ANOVA and Tukey’s HSD. A composite score integrating expression and variant burden was applied to prioritize candidate genes. Results Several non-canonical isoforms demonstrated significant enrichment for pathogenic variants and dynamic expression changes during neurodevelopment. One gene in particular showed both statistical and biological relevance, making it a strong candidate for future study. Conclusion This study supports the importance of transcript-aware variant interpretation and highlights the potential for discovering novel disease mechanisms through isoform-specific analysis in neurodevelopmental disorders.","abstract_html":"Isoform-Specific Genetic Analysis of Epigenetic Machinery Genes in Neurodevelopment and Disease Úlfur Benedikt Fjölnisson¹, Katrín Möller¹, Hans Tómas Björnsson¹,²,³ ¹ Department of Medicine, University of Iceland, Reykjavík, Iceland ² Johns Hopkins University, Baltimore, USA ³ University Hospital, Reykjavík, Iceland Introduction Missense mutations in epigenetic machinery (EM) genes are frequently associated with neurodevelopmental disorders. Studying the isoform-specific distribution of pathogenic variants and the timing of isoform expression may reveal critical mechanisms underlying these diseases. Aims To assess whether pathogenic missense variants are enriched in regions unique to non-canonical isoforms and whether these isoforms show stage-specific expression during neurodevelopment. Methods Public databases (ClinVar, gnomAD, Ensembl BioMart) were used to compute missense variant densities in non-overlapping, isoform-specific exons of EM genes. Genome-wide variant data were used to ensure sufficient coverage. Enrichment was tested using Fisher’s exact test with FDR correction. Isoform expression patterns across stages of mouse neurodevelopment were analyzed using ANOVA and Tukey’s HSD. A composite score integrating expression and variant burden was applied to prioritize candidate genes. Results Several non-canonical isoforms demonstrated significant enrichment for pathogenic variants and dynamic expression changes during neurodevelopment. One gene in particular showed both statistical and biological relevance, making it a strong candidate for future study. Conclusion This study supports the importance of transcript-aware variant interpretation and highlights the potential for discovering novel disease mechanisms through isoform-specific analysis in neurodevelopmental disorders.","abstract_has_math":false,"creators":["Úlfur Benedikt Fjölnisson 2003-"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Háskóli Íslands"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-05-20T13:28:05Z","date_published":"2025-05-20T13:28:05Z","updated_at":"2026-07-27T21:39:44Z","subjects":["Læknisfræði","Stökkbreytingar","Taugaþroskaraskanir","Erfðabreytingar"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1946/50267","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Háskóli Íslands"]},{"key":"dc:creator","label":"Author","values":["Úlfur Benedikt Fjölnisson 2003-"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-05-20T13:28:04Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2025-05-20T13:28:04Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-05-20T13:28:05Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Læknisfræði","Stökkbreytingar","Taugaþroskaraskanir","Erfðabreytingar"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1946/50267"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Isoform-Specific Genetic Analysis of Epigenetic Machinery Genes in Neurodevelopment and Disease Úlfur Benedikt Fjölnisson¹, Katrín Möller¹, Hans Tómas Björnsson¹,²,³ ¹ Department of Medicine, University of Iceland, Reykjavík, Iceland ² Johns Hopkins University, Baltimore, USA ³ University Hospital, Reykjavík, Iceland Introduction Missense mutations in epigenetic machinery (EM) genes are frequently associated with neurodevelopmental disorders. Studying the isoform-specific distribution of pathogenic variants and the timing of isoform expression may reveal critical mechanisms underlying these diseases. Aims To assess whether pathogenic missense variants are enriched in regions unique to non-canonical isoforms and whether these isoforms show stage-specific expression during neurodevelopment. Methods Public databases (ClinVar, gnomAD, Ensembl BioMart) were used to compute missense variant densities in non-overlapping, isoform-specific exons of EM genes. Genome-wide variant data were used to ensure sufficient coverage. Enrichment was tested using Fisher’s exact test with FDR correction. Isoform expression patterns across stages of mouse neurodevelopment were analyzed using ANOVA and Tukey’s HSD. A composite score integrating expression and variant burden was applied to prioritize candidate genes. Results Several non-canonical isoforms demonstrated significant enrichment for pathogenic variants and dynamic expression changes during neurodevelopment. One gene in particular showed both statistical and biological relevance, making it a strong candidate for future study. Conclusion This study supports the importance of transcript-aware variant interpretation and highlights the potential for discovering novel disease mechanisms through isoform-specific analysis in neurodevelopmental disorders.","Notkun mismunandi ísóforma utangenaerfðakerfisins við taugaþroska og mikilvægi þeirra í sjúkdómum tengdum utangenaerfðakerfinu Úlfur Benedikt Fjölnisson¹, Katrín Möller¹, Hans Tómas Björnsson¹,²,³ ¹ Læknadeild Háskóla Íslands, Reykjavík, Ísland ² Johns Hopkins University, Baltimore, Bandaríkin ³ Landspítali, Reykjavík, Ísland Inngangur Stökkbreytingar í genum utangenakerfisins (EM) tengjast oft taugaþroskaröskunum. Skilningur á dreifingu meinvaldandi stökkbreytinga í mismunandi ísóformum og tímasetningu tjáningar þeirra gæti varpað ljósi á undirliggjandi sjúkdómsferla. Markmið Að kanna hvort meinvaldandi mispörunarstökkbreytingar safnist í svæðum sem eru sértæk fyrir óhefðbundin ísóform og hvort slík ísóform sýni þroskastigbundna tjáningu í taugaþroska. Aðferðir Notuð voru gagnasöfnin ClinVar, gnomAD og Ensembl BioMart til að greina þéttni mispörunarbreytinga í exónum sem eru sértæk fyrir einstök ísóform og skarast ekki við önnur ísóform í EM-genum og í öllu erfðamenginu. Notast var við gögn úr heildarerfðamengisraðgreiningu þar sem óhefðbundnir exónar finnast sjaldan í exómgögnum. Fisher-próf með FDR-leiðréttingu var notað til að meta tölfræðilega marktæka auðgun meinvaldandi breytinga. Tjáning ísóforma yfir þroskastig (NPC, dagur 3, 6 og 12) var metin með ANOVA og Tukey HSD prófum. Samsett stig voru reiknuð út frá tjáningarbreytingum og breytileika til að forgangsraða áhugaverðum genum. Niðurstöður Fjöldi óhefðbundinna ísóforma sýndi marktæka auðgun meinvaldandi breytinga og aukna tjáningu á ákveðnum stigum taugaþroska. Eitt gen stóð sérstaklega upp úr og virðist innihalda ísóform með mögulegt sjúkdómsfræðilegt gildi. Ályktanir Niðurstöðurnar styðja mikilvægi þess að beita ísóforma- og exónu-nákvæmri greiningu til að finna erfðabreytingar sem annars væru faldar í hefðbundinni auðgunargreiningu. Slík greining getur leitt í ljós breytileika sem er falinn í hefðbundnum erfðafræðilegum greiningum og dregið fram nýja þætti í sjúkdómsmyndun taugaþroskaraskana."]},{"key":"dc:title","label":"Title","values":["Isoform-Specific Variant and Expression Analysis of Epigenetic Genes in Neurodevelopment and Disease","Ísóformasértæk greining á stökkbreytingum og tjáningu gena utangenakerfisins við taugaþroska og tengsl við sjúkdóma"]}]}],"canonical_facts":{"dc:contributor":["Háskóli Íslands"],"dc:creator":["Úlfur Benedikt Fjölnisson 2003-"],"dc:date.accessioned":["2025-05-20T13:28:04Z"],"dc:date.available":["2025-05-20T13:28:04Z"],"dc:date.issued":["2025-05-20T13:28:05Z"],"dc:description.abstract":["Isoform-Specific Genetic Analysis of Epigenetic Machinery Genes in Neurodevelopment and Disease Úlfur Benedikt Fjölnisson¹, Katrín Möller¹, Hans Tómas Björnsson¹,²,³ ¹ Department of Medicine, University of Iceland, Reykjavík, Iceland ² Johns Hopkins University, Baltimore, USA ³ University Hospital, Reykjavík, Iceland Introduction Missense mutations in epigenetic machinery (EM) genes are frequently associated with neurodevelopmental disorders. Studying the isoform-specific distribution of pathogenic variants and the timing of isoform expression may reveal critical mechanisms underlying these diseases. Aims To assess whether pathogenic missense variants are enriched in regions unique to non-canonical isoforms and whether these isoforms show stage-specific expression during neurodevelopment. Methods Public databases (ClinVar, gnomAD, Ensembl BioMart) were used to compute missense variant densities in non-overlapping, isoform-specific exons of EM genes. Genome-wide variant data were used to ensure sufficient coverage. Enrichment was tested using Fisher’s exact test with FDR correction. Isoform expression patterns across stages of mouse neurodevelopment were analyzed using ANOVA and Tukey’s HSD. A composite score integrating expression and variant burden was applied to prioritize candidate genes. Results Several non-canonical isoforms demonstrated significant enrichment for pathogenic variants and dynamic expression changes during neurodevelopment. One gene in particular showed both statistical and biological relevance, making it a strong candidate for future study. Conclusion This study supports the importance of transcript-aware variant interpretation and highlights the potential for discovering novel disease mechanisms through isoform-specific analysis in neurodevelopmental disorders.","Notkun mismunandi ísóforma utangenaerfðakerfisins við taugaþroska og mikilvægi þeirra í sjúkdómum tengdum utangenaerfðakerfinu Úlfur Benedikt Fjölnisson¹, Katrín Möller¹, Hans Tómas Björnsson¹,²,³ ¹ Læknadeild Háskóla Íslands, Reykjavík, Ísland ² Johns Hopkins University, Baltimore, Bandaríkin ³ Landspítali, Reykjavík, Ísland Inngangur Stökkbreytingar í genum utangenakerfisins (EM) tengjast oft taugaþroskaröskunum. Skilningur á dreifingu meinvaldandi stökkbreytinga í mismunandi ísóformum og tímasetningu tjáningar þeirra gæti varpað ljósi á undirliggjandi sjúkdómsferla. Markmið Að kanna hvort meinvaldandi mispörunarstökkbreytingar safnist í svæðum sem eru sértæk fyrir óhefðbundin ísóform og hvort slík ísóform sýni þroskastigbundna tjáningu í taugaþroska. Aðferðir Notuð voru gagnasöfnin ClinVar, gnomAD og Ensembl BioMart til að greina þéttni mispörunarbreytinga í exónum sem eru sértæk fyrir einstök ísóform og skarast ekki við önnur ísóform í EM-genum og í öllu erfðamenginu. Notast var við gögn úr heildarerfðamengisraðgreiningu þar sem óhefðbundnir exónar finnast sjaldan í exómgögnum. Fisher-próf með FDR-leiðréttingu var notað til að meta tölfræðilega marktæka auðgun meinvaldandi breytinga. Tjáning ísóforma yfir þroskastig (NPC, dagur 3, 6 og 12) var metin með ANOVA og Tukey HSD prófum. Samsett stig voru reiknuð út frá tjáningarbreytingum og breytileika til að forgangsraða áhugaverðum genum. Niðurstöður Fjöldi óhefðbundinna ísóforma sýndi marktæka auðgun meinvaldandi breytinga og aukna tjáningu á ákveðnum stigum taugaþroska. Eitt gen stóð sérstaklega upp úr og virðist innihalda ísóform með mögulegt sjúkdómsfræðilegt gildi. Ályktanir Niðurstöðurnar styðja mikilvægi þess að beita ísóforma- og exónu-nákvæmri greiningu til að finna erfðabreytingar sem annars væru faldar í hefðbundinni auðgunargreiningu. Slík greining getur leitt í ljós breytileika sem er falinn í hefðbundnum erfðafræðilegum greiningum og dregið fram nýja þætti í sjúkdómsmyndun taugaþroskaraskana."],"dc:identifier.uri":["https://hdl.handle.net/1946/50267"],"dc:language.iso":["en"],"dc:subject":["Læknisfræði","Stökkbreytingar","Taugaþroskaraskanir","Erfðabreytingar"],"dc:title":["Isoform-Specific Variant and Expression Analysis of Epigenetic Genes in Neurodevelopment and Disease","Ísóformasértæk greining á stökkbreytingum og tjáningu gena utangenakerfisins við taugaþroska og tengsl við sjúkdóma"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:39:44Z"}