DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder

Kathleen Rooney; Liselot van der Laan; Slavica Trajkova; Sadegheh Haghshenas; Raissa Relator; Peter Lauffer; Niels Vos; Michael A Levy; Nicola Brunetti-Pierri; Gaetano Terrone; Cyril Mignot; Boris Keren; Thierry B de Villemeur; Catharina M L Volker-Touw; Nienke Verbeek; Jasper J van der Smagt; Renske Oegema; Alfredo Brusco; Giovanni B Ferrero; Mala Misra-Isrie; Ron Hochstenbach; Mariëlle Alders; Marcel M A M Mannens; Bekim Sadikovic; Mieke M van Haelst; Peter Henneman

doi:10.1016/j.gim.2023.100871

DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder

Genet Med. 2023 Aug;25(8):100871. doi: 10.1016/j.gim.2023.100871. Epub 2023 Apr 28.

Authors

Kathleen Rooney¹, Liselot van der Laan², Slavica Trajkova³, Sadegheh Haghshenas⁴, Raissa Relator⁴, Peter Lauffer², Niels Vos², Michael A Levy⁴, Nicola Brunetti-Pierri⁵, Gaetano Terrone⁶, Cyril Mignot⁷, Boris Keren⁷, Thierry B de Villemeur⁸, Catharina M L Volker-Touw⁹, Nienke Verbeek⁹, Jasper J van der Smagt⁹, Renske Oegema⁹, Alfredo Brusco¹⁰, Giovanni B Ferrero¹¹, Mala Misra-Isrie², Ron Hochstenbach², Mariëlle Alders², Marcel M A M Mannens², Bekim Sadikovic¹², Mieke M van Haelst², Peter Henneman¹³

Affiliations

¹ Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
² Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
³ Department of Medical Sciences, University of Torino, Torino, Italy.
⁴ Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada.
⁵ Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Department of Translational Medicine, Federico II University, Naples, Italy.
⁶ Department of Translational Medicine, Federico II University, Naples, Italy.
⁷ Assistance Publique-Hopitaux de Paris, Sorbonne Université, Departement de Génétique, Groupe Hospitalier Pitie-Salpetriere et Hopital Trousseau, Paris, France.
⁸ Sorbonne Université, APHP, Hôpital Trousseau, Service de neuropédiatrie, Paris, France.
⁹ Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
¹⁰ Department of Medical Sciences, University of Torino, Torino, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.
¹¹ Department of Clinical and Biological Science, University of Torino, Torino, Italy.
¹² Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada. Electronic address: bekim.sadikovic@lhsc.on.ca.
¹³ Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: p.henneman@amsterdamumc.nl.

PMID: 37120726
DOI: 10.1016/j.gim.2023.100871

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 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.

Keywords: CNV; DNA methylation; Episignature; HNRNPU; Neurodevelopmental disorder.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
DNA Methylation* / genetics
Epigenomics
Humans
Neurodevelopmental Disorders* / genetics
Neurodevelopmental Disorders* / pathology
Phenotype

Substances

Biomarkers