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

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 KerenHester 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^*

^*Corresponding author for this work

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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.

Original language	English
Article number	100380
Journal	Human Genetics and Genomics Advances
Volume	6
Issue number	1
DOIs	https://doi.org/10.1016/j.xhgg.2024.100380
Publication status	Published - 9 Jan 2025

Keywords

CUL3
DNA methylation
episignature
genotype-phenotype correlation
intellectual disability
NEDAUS

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PIIS2666247724001209Final published version, 3.81 MBLicence: CC BY

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van der Laan, L., Silva, A., Kleinendorst, L., Rooney, K., Haghshenas, S., Lauffer, P., Alanay, Y., Bhai, P., Brusco, A., de Munnik, S., de Vries, B. B. A., Vega, A. D., Engelen, M., Herkert, J. C., Hochstenbach, R., Hopman, S., Kant, S. G., Kira, R., Kato, M., ... Henneman, P. (2025). CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature. Human Genetics and Genomics Advances, 6(1), Article 100380. https://doi.org/10.1016/j.xhgg.2024.100380

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

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, episignature, genotype-phenotype correlation, intellectual disability, NEDAUS",

author = "{van der Laan}, Liselot and Anan{\'i}lia Silva and Lotte Kleinendorst and Kathleen Rooney and Sadegheh Haghshenas and Peter Lauffer and Yasemin Alanay and Pratibha Bhai and Alfredo Brusco and {de Munnik}, Sonja and {de Vries}, {Bert B.A.} and Vega, {Angelica Delgado} and Marc Engelen and Herkert, {Johanna C.} and Ron Hochstenbach and Saskia Hopman and Kant, {Sarina G.} and Ryutaro Kira and Mitsuhiro Kato and Boris Keren and Kroes, {Hester Y.} and Levy, {Michael A.} and Ngu Lock-Hock and Maas, {Saskia M.} and Mancini, {Grazia M.S.} and Carlo Marcelis and Naomichi Matsumoto and Takeshi Mizuguchi and Alessandro Mussa and Cyril Mignot and Anu N{\"a}rhi and Ann Nordgren and Rolph Pfundt and Polstra, {Abeltje M.} and Slavica Trajkova and {van Bever}, Yolande and {Jos{\'e} van den Boogaard}, Marie and {van der Smagt}, {Jasper J.} and Barakat, {Tahsin Stefan} and Mari{\"e}lle Alders and Mannens, {Marcel M.A.M.} and Bekim Sadikovic and {van Haelst}, {Mieke M.} and Peter Henneman",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2025",

month = jan,

day = "9",

doi = "10.1016/j.xhgg.2024.100380",

language = "English",

volume = "6",

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van der Laan, L, Silva, A, Kleinendorst, L, Rooney, K, Haghshenas, S, Lauffer, P, Alanay, Y, Bhai, P, Brusco, A, de Munnik, S, de Vries, BBA, Vega, AD, Engelen, M, Herkert, JC, Hochstenbach, R, Hopman, S, Kant, SG, Kira, R, Kato, M, Keren, B, Kroes, HY, Levy, MA, Lock-Hock, N, Maas, SM, Mancini, GMS, Marcelis, C, Matsumoto, N, Mizuguchi, T, Mussa, A, Mignot, C, Närhi, A, Nordgren, A, Pfundt, R, Polstra, AM, Trajkova, S, van Bever, Y, José van den Boogaard, M , van der Smagt, JJ, Barakat, TS, Alders, M, Mannens, MMAM, Sadikovic, B, van Haelst, MM & Henneman, P 2025, 'CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature', Human Genetics and Genomics Advances, vol. 6, no. 1, 100380. https://doi.org/10.1016/j.xhgg.2024.100380

CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature. / van der Laan, Liselot; Silva, Ananília; Kleinendorst, Lotte et al.
In: Human Genetics and Genomics Advances, Vol. 6, No. 1, 100380, 09.01.2025.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - CUL3-related neurodevelopmental disorder

T2 - Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature

AU - van der Laan, Liselot

AU - Silva, Ananília

AU - Kleinendorst, Lotte

AU - Rooney, Kathleen

AU - Haghshenas, Sadegheh

AU - Lauffer, Peter

AU - Alanay, Yasemin

AU - Bhai, Pratibha

AU - Brusco, Alfredo

AU - de Munnik, Sonja

AU - de Vries, Bert B.A.

AU - Vega, Angelica Delgado

AU - Engelen, Marc

AU - Herkert, Johanna C.

AU - Hochstenbach, Ron

AU - Hopman, Saskia

AU - Kant, Sarina G.

AU - Kira, Ryutaro

AU - Kato, Mitsuhiro

AU - Keren, Boris

AU - Kroes, Hester Y.

AU - Levy, Michael A.

AU - Lock-Hock, Ngu

AU - Maas, Saskia M.

AU - Mancini, Grazia M.S.

AU - Marcelis, Carlo

AU - Matsumoto, Naomichi

AU - Mizuguchi, Takeshi

AU - Mussa, Alessandro

AU - Mignot, Cyril

AU - Närhi, Anu

AU - Nordgren, Ann

AU - Pfundt, Rolph

AU - Polstra, Abeltje M.

AU - Trajkova, Slavica

AU - van Bever, Yolande

AU - José van den Boogaard, Marie

AU - van der Smagt, Jasper J.

AU - Barakat, Tahsin Stefan

AU - Alders, Mariëlle

AU - Mannens, Marcel M.A.M.

AU - Sadikovic, Bekim

AU - van Haelst, Mieke M.

AU - Henneman, Peter

PY - 2025/1/9

Y1 - 2025/1/9

N2 - 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.

AB - 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.

KW - CUL3

KW - DNA methylation

KW - episignature

KW - genotype-phenotype correlation

KW - intellectual disability

KW - NEDAUS

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U2 - 10.1016/j.xhgg.2024.100380

DO - 10.1016/j.xhgg.2024.100380

M3 - Article

C2 - 39501558

AN - SCOPUS:85209580203

SN - 2666-2477

VL - 6

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

IS - 1

M1 - 100380

ER -

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

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