CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature

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.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2024-11-04
DOI
https://doi.org/10.1016/j.xhgg.2024.100380
Citations
5
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
2.75

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article

CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature

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CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature

Sonja de Munnik, Marcel M. A. M. Mannens, Grazia M.S. Mancini, Yolande van Bever, Anu Närhi, Rolph Pfundt, Sadegheh Haghshenas, Ryutaro Kira, Abeltje M. Polstra, Saskia M Maas, Slavica Trajkova, Lotte Kleinendorst, Ana Vega, Yasemin Alanay, Mieke M. van Haelst, Carlo Marcelis, Tahsin Stefan Barakat, Mariëlle Alders, Peter Lauffer, Mitsuhiro Kato, Marc Engelen, Johanna C. Herkert, Peter Henneman, Liselot van der Laan, Pratibha Bhai, Ananília Silva, Bert B.A. de Vries, Saskia Hopman, Ann Nordgren, Bekim Sadiković, Cyril Mignot, Lock Hock Ngu, Sarina G. Kant, Naomichi Matsumoto, Kathleen Rooney, Ron Hochstenbach, Boris Keren, Alfredo Brusco, Hester Y. Kroes, M. J. van den Boogaard, Takeshi Mizuguchi, Michael A. Levy, Alessandro Mussa, Jasper J. van der Smagt
article en
5 citations

Abstract

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.

Human Genetics and Genomics AdvancesVol. 6(1)
SHOWA Medical University (JP), University Medical Center Groningen (NL), University of Helsinki (FI), Radboud University Nijmegen (NL), University of Groningen (NL), Hospital Kuala Lumpur (MY), Helsinki University Hospital (FI), London Health Sciences Centre (CA), Erasmus MC (NL), Radboud University Medical Center (NL), University Medical Center Utrecht (NL), Sorbonne Université (FR), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Assistance Publique – Hôpitaux de Paris (FR), Fukuoka Children's Hospital and Medical Center for Infectious Diseases (JP), University of Turin (IT), Yokohama City University (JP)
Citizens United for Research in Epilepsy, Genome Canada, Ontario Genomics, Amsterdam University Medical Centers, Government of Canada, Ontario Genomics Institute, ZonMw, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Japan Society for the Promotion of Science
Zero hunger
Openalex Percentile: Top 9%
Genomics and Rare Diseases
2.75
DOIOpen Access PDFOpenAlex
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