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

IF 3.3 Q2 GENETICS & HEREDITY HGG Advances Pub Date : 2024-11-04 DOI:10.1016/j.xhgg.2024.100380
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
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引用次数: 0

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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CUL3相关神经发育障碍:20个新个体的临床表型及潜在表型相关表征的鉴定。
伴有或不伴有自闭症或癫痫发作的神经发育障碍(NEDAUS;OMIM #619239)是一种神经发育障碍,其特征是全身发育迟缓、语言发育迟缓、癫痫发作、自闭症特征和/或行为异常。它是由 CUL3(Cullin-3 泛素连接酶;OMIM #603136)单倍体缺陷引起的。我们收集了 26 例携带 CUL3 基因致病变体和意义不确定变体 (VUS) 的患者的临床和分子数据,其中包括 20 例之前未报道的病例。通过将他们的DNA甲基化(DNAm)分类器与健康对照组和其他具有既定表征特征的神经发育疾病的DNA甲基化分类器进行比较,我们旨在创建一种诊断生物标志物(表征特征),并获得更多有关分子病理生理学的知识。我们发现了一种针对CUL3致病变异患者的敏感而特异的DNAm表观特征,并利用它对CUL3基因携带VUS的患者进行了重新分类。表观基因组对比分析表明,NEDAUS与其他几种罕见的遗传性神经发育疾病具有相似性,这些疾病的表观特征均在之前已被确定,这凸显了我们的发现具有更广泛的意义。此外,我们还进行了基因型与表型的相关性研究,以解释不同病例临床表现的差异。我们发现了一个高度准确的 DNAm 表征,可作为 NEDAUS 的可靠诊断生物标志物。此外,我们还发现了 20 例新的 NEDAUS 患者,并确认了 5 例以前报告过的 NEDAUS 病例,从而拓宽了表型谱。
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来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
期刊最新文献
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