مورد إلكتروني
Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects
| العنوان: | Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects |
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| المؤلفون: | Duncan, A.R. (Anna R.), Vitobello, A. (Antonio), Collins, S.C. (Stephan C.), Vancollie, V.E. (Valerie E.), Lelliott, C.J. (Christopher J.), Rodan, L. (Lance), Shi, J. (Jiahai), Seman, A.R. (Ann R.), Agolini, E. (Emanuele), Novelli, A. (Antonio), Prontera, P. (Paolo), Guillen Sacoto, M.J. (Maria J.), Santiago-Sim, T. (Teresa), Trimouille, A. (Aurélien), Goizet, C. (Cyril), Nizon, M. (Mathilde), Bruel, A.-L. (Ange-Line), Philippe, C. (Christophe), Grant, P.E. (Patricia E.), Wojcik, M.H. (Monica H.), Stoler, J. (Joan), Genetti, C.A. (Casie A.), Dooren, M.F. (Marieke) van, Maas, S.M. (Saskia), Alders, M. (Mariëlle), Faivre, L. (Laurence), Sorlin, A. (Arthur), Yoon, G. (Grace), Yalcin, B. (Binnaz), Agrawal, P.B. (Pankaj B.) |
| بيانات النشر: | 2020-12-03 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/-), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery. |
| مصطلحات الفهرس: | agenesis of the corpus callosum, dysmorphic hippocampi, global developmental delay, heterozygous variant, intellectual disability, JMJD2B, KDM4B, neurodevelopmental disorder, info:eu-repo/semantics/article |
| DOI: | 10.1016.j.ajhg.2020.11.001 |
| URL: | |
| الإتاحة: | Open access content. Open access content info:eu-repo/semantics/openAccess |
| ملاحظة: | application/pdf American Journal of Human Genetics vol. 107 no. 6, pp. 1170-1177 English |
| أرقام أخرى: | QGQ oai:repub.eur.nl:132482 doi:10.1016/j.ajhg.2020.11.001 urn:hdl:1765/132482 1236256853 |
| المصدر المساهم: | ERASMUS UNIVERSITEIT ROTTERDAM From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1236256853 |
| قاعدة البيانات: | OAIster |
| DOI: | 10.1016.j.ajhg.2020.11.001 |
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