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

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.

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