Biallelic loss-of-function variants in ZNF142 are associated with a robust DNA methylation signature affecting a limited number of genomic loci.

Journal: European journal of human genetics : EJHG
Published Date: May 23, 2025

Abstract

Biallelic inactivating variants in ZNF142 underlie a clinically variable neurodevelopmental disorder. ZNF142 is a zinc-finger transcription factor with potential roles on chromatin organization, implying a possible association of ZNF142 loss of function with perturbed genome-wide DNA methylation (DNAm) pattern. We performed EPIC array-based methylation profiling of peripheral blood-derived DNA samples from 27 individuals with biallelic ZNF142 inactivating variants, together with 6 heterozygous carriers and 40 controls. A DNAm signature discovery pipeline was applied by using 440 controls for discovery and validation analyses, and a machine-learning model was trained to classify 8 individuals carrying ZNF142 variants of uncertain clinical significance. Analyses directed to explore the genome-wide DNAm landscape in affected individuals revealed 88 differentially methylated probes constituting the minimal informative set specific to ZNF142 loss of function. This reproducible pattern of DNAm changes involved regulatory regions of a small number of genes. The DNAm signature derived from peripheral blood allowed us to diagnose individuals carrying biallelic inactivating ZNF142 variants when applied to fibroblasts. Our findings provide evidence that biallelic loss-of-function ZNF142 variants result in a specific and robust DNAm signature. The identified DNAm pattern suggests occurrence of a methylation disturbance involving a small number of loci that appears to be shared by different cell lineages.

Authors

  • Mathis Hildonen
    Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
  • Andrea Ciolfi
    Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy.
  • Marco Ferilli
    Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy.
  • Camilla Cappelletti
    Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy.
  • Chadi Al Alam
    Department of Pediatric Neurology, American center for Psychiatry and Neurology, Abu Dhabi, UAE.
  • David J Amor
    Department of Paediatrics, University of Melbourne, Murdoch Children's Research Institute, Melbourne, Australia.
  • Tahsin Stefan Barakat
    Deparment of Clinical Genetics, Erasmus MC, 3000CA, Rotterdam, The Netherlands.
  • Valérie Benoit
    IPG, Centre for Human Genetics, Charleroi, Belgium.
  • Ohad Shmuel Birk
    Genetics Institute, Soroka University Medical Center, Beer-Sheva, Israel.
  • Bert Callewaert
    Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • Ana Cazurro-Gutiérrez
    Paediatric Neurology Research Group, Vall d'Hebron Institut de Recerca, 08035, Barcelona, Spain.
  • Matthias De Wachter
    Department of Child Neurology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
  • Martine Doco-Fenzy
    SFR CAP SANTE, Service de génétique CHU Reims, 51092, Reims, France.
  • Paulino Gómez-Puertas
    Molecular Modeling Group, Centro de Biología Molecular Severo Ochoa, CBMSO (CSIC-UAM), E-28049, Madrid, Spain.
  • Trine Bjørg Hammer
    Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
  • Rami Abou Jamra
    Institute of Human Genetics, University of Leipzig Medical Center Leipzig, 04103, Leipzig, Germany.
  • Rauan Kaiyrzhanov
    Department of Neuromuscular Disorders, University College London Institute of Neurology, WC1N 3BG, London, UK.
  • Shinichi Kameyama
    Department of Human Genetics, Yokohama City University Graduate School of Medicine, 236-0004, Yokohama, Japan.
  • Boris Keren
    Department of Medical Genetics, Pitié-Salpêtrière Hospital, AP-HP.Sorbonne Université, 75013, Paris, France.
  • Christina Kresge
    Rutgers New Jersey Medical School, Newark, NJ, USA.
  • Ilona Krey
    Institute of Human Genetics, University of Leipzig Medical Center Leipzig, 04103, Leipzig, Germany.
  • Damien Lederer
    IPG, Centre for Human Genetics, Charleroi, Belgium.
  • Iñigo Marcos-Alcalde
    Molecular Modeling Group, Centro de Biología Molecular Severo Ochoa, CBMSO (CSIC-UAM), E-28049, Madrid, Spain.
  • Reza Maroofian
    Department of Neuromuscular Disorders, University College London Institute of Neurology, WC1N 3BG, London, UK.
  • Naomichi Matsumoto
    Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. Electronic address: naomat@yokohama-cu.ac.jp.
  • Takeshi Mizuguchi
    Department of Human Genetics, Yokohama City University Graduate School of Medicine, 236-0004, Yokohama, Japan.
  • Lip-Hen Moey
    Department of Clinical Genetics, Penang Hospital, 10450, Georgetown, Malaysia.
  • Angela Morgan
    Speech and Language, Murdoch Children's Research Institute, 3052, Melbourne, Australia.
  • Francina Munell
    Paediatric Neurology Research Group, Vall d'Hebron Institut de Recerca, 08035, Barcelona, Spain.
  • Konrad Platzer
    Institute of Human Genetics, University of Leipzig Medical Center Leipzig, 04103, Leipzig, Germany.
  • Beth A Pletcher
    Rutgers New Jersey Medical School, Newark, NJ, USA.
  • David Ros-Pardo
    Molecular Modeling Group, Centro de Biología Molecular Severo Ochoa, CBMSO (CSIC-UAM), E-28049, Madrid, Spain.
  • Lynne Rumping
    Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650, Edegem, Belgium.
  • Katalin Szakszon
    University of Debrecen, Faculty of Medicine, Clinical Center, Institute of Paediatrics, 4032, Debrecen, Hungary.
  • Kristof Van Schil
    Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650, Edegem, Belgium.
  • Edgard Verdura
    Paediatric Neurology Research Group, Vall d'Hebron Institut de Recerca, 08035, Barcelona, Spain.
  • Julie Vogt
    West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, B15 2TG, Birmingham, UK.
  • Evangeline Wassmer
    Neurology, Birmingham Women's and Children's Hospital, B4 6 NH, Birmingham, UK.
  • Mina Zamani
    Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, 10003, USA.
  • Zeynep Tümer
    Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark. Zeynep.tumer@regionh.dk.
  • Marco Tartaglia
    Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy. marco.tartaglia@opbg.net.

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