Isoform-Specific Variant and Expression Analysis of Epigenetic Genes in Neurodevelopment and Disease

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.

Author dc:creator

• Úlfur Benedikt Fjölnisson 2003-

Contributors dc:contributor

• Háskóli Íslands

• Læknisfræði
• Stökkbreytingar
• Taugaþroskaraskanir
• Erfðabreytingar

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/1946/50267

OAI identifier oai:identifier

oai:skemman.is:1946/50267