TY - JOUR
T1 - DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder
AU - Rooney, Kathleen
AU - van der Laan, Liselot
AU - Trajkova, Slavica
AU - Haghshenas, Sadegheh
AU - Relator, Raissa
AU - Lauffer, Peter
AU - Vos, Niels
AU - Levy, Michael A.
AU - Brunetti-Pierri, Nicola
AU - Terrone, Gaetano
AU - Mignot, Cyril
AU - Keren, Boris
AU - de Villemeur, Thierry B.
AU - Volker-Touw, Catharina M. L.
AU - Verbeek, Nienke
AU - van der Smagt, Jasper J.
AU - Oegema, Renske
AU - Brusco, Alfredo
AU - Ferrero, Giovanni B.
AU - Misra-Isrie, Mala
AU - Hochstenbach, Ron
AU - Alders, Mariëlle
AU - Mannens, Marcel M. A. M.
AU - Sadikovic, Bekim
AU - van Haelst, Mieke M.
AU - Henneman, Peter
N1 - Funding Information: The authors would like to thank the participants and their families described in this study. Funding for this study is provided in part by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188) and Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) PRIN2020 code 20203P8C3X. Conceptualization: K.R. L.v.d.L. M.A. M.M.A.M.M. B.S. M.M.v.H. P.H.; Data Curation: K.R. L.v.d.L. S.H. R.R. M.A.L.; Formal Analysis: K.R. L.v.d.L. S.H. R.R. M.A.L.; Investigation: L.v.d.L. S.T. N.V. P.L. N.B.-P. G.T. C.M. B.K. T.B.d.V. C.M.L.V.-T. N.V. J.J.v.d.S. R.O. A.B. G.B.F. M.M.-I. R.H. M.A. M.M.v.H.; Methodology: K.R. M.M.A.M.M. B.S. P.H. M.M.v.H.; Project Administration: M.M.A.M.M. B.S. M.M.v.H. P.H.; Supervision: M.M.A.M.M. B.S. M.M.v.H. P.H.; Validation: K.R. L.v.d.L.; Visualization: K.R. L.v.d.L.; Writing-original draft: K.R. L.v.d.L.; Writing-review and editing: K.R. L.v.d.L. S.T. P.L. R.H. M.M.A.M.M. B.S. M.M.v.H. P.H. The study was conducted in accordance with the regulations of the Western University Research Ethics Board (REB116108 and REB106302) and The Medical Ethical Committee (METC) of the Amsterdam UMC, location AMC. METC approval (anonymous study, further study in line with a clinical question). We obtained written informed consent from the participants or their substitute decision maker to publish patients’ clinical and genetic information. Explicit consent for the publication of individuals’ photographs was obtained separately. The authors declare no conflicts of interest. Funding Information: Funding for this study is provided in part by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188) and Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) PRIN2020 code 20203P8C3X. Publisher Copyright: © 2023 American College of Medical Genetics and Genomics
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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 multicenter collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort with 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 EpiSign diagnostic test.
AB - 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 multicenter collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort with 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 EpiSign diagnostic test.
KW - CNV
KW - DNA methylation
KW - Episignature
KW - HNRNPU
KW - Neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85160663444&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.gim.2023.100871
DO - https://doi.org/10.1016/j.gim.2023.100871
M3 - Article
C2 - 37120726
SN - 1098-3600
VL - 25
JO - Genetics in medicine
JF - Genetics in medicine
IS - 8
M1 - 100871
ER -