CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature
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...
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Elsevier
2025-01-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247724001209 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Liselot van der Laan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4d2c1e6771da43cd9a0c73ae48b1b4d3 |
| institution | Kabale University |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj-art-4d2c1e6771da43cd9a0c73ae48b1b4d32024-11-21T06:06:32ZengElsevierHGG Advances2666-24772025-01-0161100380CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignatureLiselot van der Laan0Ananília Silva1Lotte Kleinendorst2Kathleen Rooney3Sadegheh Haghshenas4Peter Lauffer5Yasemin Alanay6Pratibha Bhai7Alfredo Brusco8Sonja de Munnik9Bert B.A. de Vries10Angelica Delgado Vega11Marc Engelen12Johanna C. Herkert13Ron Hochstenbach14Saskia Hopman15Sarina G. Kant16Ryutaro Kira17Mitsuhiro Kato18Boris Keren19Hester Y. Kroes20Michael A. Levy21Ngu Lock-Hock22Saskia M. Maas23Grazia M.S. Mancini24Carlo Marcelis25Naomichi Matsumoto26Takeshi Mizuguchi27Alessandro Mussa28Cyril Mignot29Anu Närhi30Ann Nordgren31Rolph Pfundt32Abeltje M. Polstra33Slavica Trajkova34Yolande van Bever35Marie José van den Boogaard36Jasper J. van der Smagt37Tahsin Stefan Barakat38Mariëlle Alders39Marcel M.A.M. Mannens40Bekim Sadikovic41Mieke M. van Haelst42Peter Henneman43Amsterdam 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 NetherlandsDepartment of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the NetherlandsAmsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the NetherlandsDepartment of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, CanadaVerspeeten Clinical Genome Centre, London Health Science Centre, London, ON, CanadaAmsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the NetherlandsDivision 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, TurkeyVerspeeten Clinical Genome Centre, London Health Science Centre, London, ON, CanadaDepartment of Medical Sciences, University of Torino, Torino, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, ItalyDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the NetherlandsDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the NetherlandsDepartment of Clinical Genetics and Genomics, Karolinska University Hospital, Department of Molecular Medicine, Karolinska Undiagnosed Disease Program, Karolinska Institutet, Stockholm, SwedenDepartment of Pediatric Neurology/Emma Children’s Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the NetherlandsAmsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Genetics, University Medical Center Utrecht, Utrecht, the NetherlandsDepartment of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the NetherlandsDepartment of Pediatric Neurology, Fukuoka Children’s Hospital, Fukuoka, JapanDepartment of Pediatrics, Showa University School of Medicine, Tokyo, JapanAssistance Publique-Hopitaux de Paris, Sorbonne Université, Departement de Génétique, Groupe Hospitalier Pitie-Salpetriere et Hopital Trousseau, Paris, FranceDepartment of Genetics, University Medical Center Utrecht, Utrecht, the NetherlandsVerspeeten Clinical Genome Centre, London Health Science Centre, London, ON, CanadaGenetics Department, Hospital Kuala Lumpur, Kuala Lumpur, MalaysiaAmsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the NetherlandsDepartment of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the NetherlandsMedical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, ItalyDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, JapanDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, JapanDepartment of Public Health and Pediatrics, Pediatric Clinical Genetics, Regina Margherita Children’s Hospital, University of Turin, Turin, ItalyAssistance Publique-Hopitaux de Paris, Sorbonne Université, Departement de Génétique, Groupe Hospitalier Pitie-Salpetriere et Hopital Trousseau, Paris, FranceDepartment of Clinical Genetics, Helsinki University Hospital, Helenski, FinlandDepartment 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, SwedenMedical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, ItalyAmsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Medical Sciences, University of Torino, Torino, ItalyDepartment of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the NetherlandsDepartment of Genetics, University Medical Center Utrecht, Utrecht, the NetherlandsDepartment of Genetics, University Medical Center Utrecht, Utrecht, the NetherlandsDepartment of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the NetherlandsAmsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the NetherlandsAmsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the NetherlandsDepartment of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada; Corresponding authorAmsterdam 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 NetherlandsAmsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666247724001209CUL3intellectual disabilityDNA methylationepisignatureNEDAUSgenotype-phenotype correlation |
| spellingShingle | 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 CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature HGG Advances CUL3 intellectual disability DNA methylation episignature NEDAUS genotype-phenotype correlation |
| title | CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature |
| title_full | CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature |
| title_fullStr | CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature |
| title_full_unstemmed | CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature |
| title_short | CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature |
| title_sort | cul3 related neurodevelopmental disorder clinical phenotype of 20 new individuals and identification of a potential phenotype associated episignature |
| topic | CUL3 intellectual disability DNA methylation episignature NEDAUS genotype-phenotype correlation |
| url | http://www.sciencedirect.com/science/article/pii/S2666247724001209 |
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