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

doi:10.1016/j.xhgg.2024.100380

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

HGG Adv. 2024 Nov 4;6(1):100380. doi: 10.1016/j.xhgg.2024.100380. Online ahead of print.

Authors

Liselot van der Laan¹, Ananília Silva², Lotte Kleinendorst³, Kathleen Rooney⁴, Sadegheh Haghshenas⁵, Peter Lauffer³, Yasemin Alanay⁶, Pratibha Bhai⁵, Alfredo Brusco⁷, Sonja de Munnik⁸, Bert B A de Vries⁸, Angelica Delgado Vega⁹, Marc Engelen¹⁰, Johanna C Herkert¹¹, Ron Hochstenbach¹², Saskia Hopman¹³, Sarina G Kant¹⁴, Ryutaro Kira¹⁵, Mitsuhiro Kato¹⁶, Boris Keren¹⁷, Hester Y Kroes¹³, Michael A Levy⁵, Ngu Lock-Hock¹⁸, Saskia M Maas³, Grazia M S Mancini¹⁴, Carlo Marcelis¹⁹, Naomichi Matsumoto²⁰, Takeshi Mizuguchi²⁰, Alessandro Mussa²¹, Cyril Mignot¹⁷, Anu Närhi²², Ann Nordgren²³, Rolph Pfundt¹⁹, Abeltje M Polstra¹², Slavica Trajkova²⁴, Yolande van Bever¹⁴, Marie José van den Boogaard¹³, Jasper J van der Smagt¹³, Tahsin Stefan Barakat¹⁴, Mariëlle Alders³, Marcel M A M Mannens³, Bekim Sadikovic²⁵, Mieke M van Haelst¹, Peter Henneman²⁶

Affiliations

¹ 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.
² Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands.
³ Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands.
⁴ Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada.
⁵ Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada.
⁶ 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.
⁷ Department of Medical Sciences, University of Torino, Torino, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.
⁸ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
⁹ Department of Clinical Genetics and Genomics, Karolinska University Hospital, Department of Molecular Medicine, Karolinska Undiagnosed Disease Program, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Department of Pediatric Neurology/Emma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, University of Amsterdam, Amsterdam, the Netherlands.
¹¹ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹² Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands.
¹³ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁴ Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
¹⁵ Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.
¹⁶ Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
¹⁷ Assistance Publique-Hopitaux de Paris, Sorbonne Université, Departement de Génétique, Groupe Hospitalier Pitie-Salpetriere et Hopital Trousseau, Paris, France.
¹⁸ Genetics Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.
¹⁹ Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.
²⁰ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
²¹ Department of Public Health and Pediatrics, Pediatric Clinical Genetics, Regina Margherita Children's Hospital, University of Turin, Turin, Italy.
²² Department of Clinical Genetics, Helsinki University Hospital, Helenski, Finland.
²³ 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.
²⁴ Department of Medical Sciences, University of Torino, Torino, Italy.
²⁵ Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada. Electronic address: bekim.sadikovic@lhsc.on.ca.
²⁶ Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands. Electronic address: p.henneman@amsterdamumc.nl.

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.

Keywords: CUL3; DNA methylation; NEDAUS; episignature; genotype-phenotype correlation; intellectual disability.