Purpose: HNRNPU haploinsufficiency is associated with Developmental and Epileptic Encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay, intellectual disability, speech impairment, and early onset epilepsy. We performed genome-wide DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnostic biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder. Methods: DNAm profiles of individuals carrying pathogenic HNRNPU variants, identified through an international multi-center collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort to 56 previously reported DNAm episignatures. Results: A robust and reproducible DNAm episignature and global DNAm profile were identified. Correlation analysis identified partial overlap and similarity of the global HNRNPU DNAm profile to several other rare disorders. Conclusion: This study demonstrates new evidence of a specific and sensitive DNAm episignature associated with pathogenic heterozygous HNRNPU-variants, establishing its utility as a clinical biomarker for the expansion of the EpiSignTM diagnostic test.
DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder / Rooney, K., van der Laan, L., Trajkova, S., Haghshenas, S., Relator, R., Lauffer, P., Vos, N., Levy, M.A., Brunetti-Pierri, N., Terrone, G., Mignot, C., Keren, B., Billette de Villemeur, T., Volker-Touw, C.M.L., Verbeek, N., van der Smagt, J.J., Oegema, R., Brusco, A., Ferrero, G.B., Misra-Isrie, M., et al.. - In: GENETICS IN MEDICINE. - ISSN 1098-3600. - (2023), p. 100871. [10.1016/j.gim.2023.100871]
DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder
Brunetti-Pierri, Nicola;Terrone, Gaetano;
2023
Abstract
Purpose: HNRNPU haploinsufficiency is associated with Developmental and Epileptic Encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay, intellectual disability, speech impairment, and early onset epilepsy. We performed genome-wide DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnostic biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder. Methods: DNAm profiles of individuals carrying pathogenic HNRNPU variants, identified through an international multi-center collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort to 56 previously reported DNAm episignatures. Results: A robust and reproducible DNAm episignature and global DNAm profile were identified. Correlation analysis identified partial overlap and similarity of the global HNRNPU DNAm profile to several other rare disorders. Conclusion: This study demonstrates new evidence of a specific and sensitive DNAm episignature associated with pathogenic heterozygous HNRNPU-variants, establishing its utility as a clinical biomarker for the expansion of the EpiSignTM diagnostic test.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
