HGG Advances (Jan 2025)
CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature
- Liselot van der Laan,
- Ananília Silva,
- Lotte Kleinendorst,
- Kathleen Rooney,
- Sadegheh Haghshenas,
- Peter Lauffer,
- Yasemin Alanay,
- Pratibha Bhai,
- Alfredo Brusco,
- Sonja de Munnik,
- Bert B.A. de Vries,
- Angelica Delgado Vega,
- Marc Engelen,
- Johanna C. Herkert,
- Ron Hochstenbach,
- Saskia Hopman,
- Sarina G. Kant,
- Ryutaro Kira,
- Mitsuhiro Kato,
- Boris Keren,
- Hester Y. Kroes,
- Michael A. Levy,
- Ngu Lock-Hock,
- Saskia M. Maas,
- Grazia M.S. Mancini,
- Carlo Marcelis,
- Naomichi Matsumoto,
- Takeshi Mizuguchi,
- Alessandro Mussa,
- Cyril Mignot,
- Anu Närhi,
- Ann Nordgren,
- Rolph Pfundt,
- Abeltje M. Polstra,
- Slavica Trajkova,
- Yolande van Bever,
- Marie José van den Boogaard,
- Jasper J. van der Smagt,
- Tahsin Stefan Barakat,
- Mariëlle Alders,
- Marcel M.A.M. Mannens,
- Bekim Sadikovic,
- Mieke M. van Haelst,
- Peter Henneman
Affiliations
- Liselot van der Laan
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands
- Ananília Silva
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands
- Lotte Kleinendorst
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
- Kathleen Rooney
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada
- Sadegheh Haghshenas
- Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada
- Peter Lauffer
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
- Yasemin Alanay
- Division of Pediatric Genetics, Department of Pediatrics, Acibadem University, School of Medicine, Istanbul, Turkey; Rare Diseases and Orphan Drugs Application and Research Center-ACURARE, Acibadem University, Istanbul, Turkey
- Pratibha Bhai
- Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada
- Alfredo Brusco
- Department of Medical Sciences, University of Torino, Torino, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy
- Sonja de Munnik
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
- Bert B.A. de Vries
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
- Angelica Delgado Vega
- Department of Clinical Genetics and Genomics, Karolinska University Hospital, Department of Molecular Medicine, Karolinska Undiagnosed Disease Program, Karolinska Institutet, Stockholm, Sweden
- Marc Engelen
- Department of Pediatric Neurology/Emma Children’s Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, University of Amsterdam, Amsterdam, the Netherlands
- Johanna C. Herkert
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Ron Hochstenbach
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands
- Saskia Hopman
- Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
- Sarina G. Kant
- Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
- Ryutaro Kira
- Department of Pediatric Neurology, Fukuoka Children’s Hospital, Fukuoka, Japan
- Mitsuhiro Kato
- Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan
- Boris Keren
- Assistance Publique-Hopitaux de Paris, Sorbonne Université, Departement de Génétique, Groupe Hospitalier Pitie-Salpetriere et Hopital Trousseau, Paris, France
- Hester Y. Kroes
- Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
- Michael A. Levy
- Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada
- Ngu Lock-Hock
- Genetics Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
- Saskia M. Maas
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
- Grazia M.S. Mancini
- Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
- Carlo Marcelis
- Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy
- Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Takeshi Mizuguchi
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Alessandro Mussa
- Department of Public Health and Pediatrics, Pediatric Clinical Genetics, Regina Margherita Children’s Hospital, University of Turin, Turin, Italy
- Cyril Mignot
- Assistance Publique-Hopitaux de Paris, Sorbonne Université, Departement de Génétique, Groupe Hospitalier Pitie-Salpetriere et Hopital Trousseau, Paris, France
- Anu Närhi
- Department of Clinical Genetics, Helsinki University Hospital, Helenski, Finland
- Ann Nordgren
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Department of Biomedicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
- Rolph Pfundt
- Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy
- Abeltje M. Polstra
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands
- Slavica Trajkova
- Department of Medical Sciences, University of Torino, Torino, Italy
- Yolande van Bever
- Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
- Marie José van den Boogaard
- Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
- Jasper J. van der Smagt
- Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
- Tahsin Stefan Barakat
- Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
- Mariëlle Alders
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
- Marcel M.A.M. Mannens
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands
- Bekim Sadikovic
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada; Corresponding author
- Mieke M. van Haelst
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands
- Peter Henneman
- Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands; Corresponding author
- Journal volume & issue
-
Vol. 6,
no. 1
p. 100380
Abstract
Summary: Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency. We collected clinical and molecular data from 26 individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including 20 previously unreported cases. By comparing their DNA methylation (DNAm) classifiers with those of healthy controls and other neurodevelopmental disorders characterized by established episignatures, we aimed to create a diagnostic biomarker (episignature) and gain more knowledge of the molecular pathophysiology. We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene. Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings. In addition, we performed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases. We discovered a highly accurate DNAm episignature serving as a robust diagnostic biomarker for NEDAUS. Furthermore, we broadened the phenotypic spectrum by identifying 20 new individuals and confirming five previously reported cases of NEDAUS.
