TY - JOUR
T1 - Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects
AU - Duncan, Anna R.
AU - Vitobello, Antonio
AU - Collins, Stephan C.
AU - Vancollie, Valerie E.
AU - Lelliott, Christopher J.
AU - Rodan, Lance
AU - Shi, Jiahai
AU - Seman, Ann R.
AU - Agolini, Emanuele
AU - Novelli, Antonio
AU - Prontera, Paolo
AU - Guillen Sacoto, Maria J.
AU - Santiago-Sim, Teresa
AU - Trimouille, Aurélien
AU - Goizet, Cyril
AU - Nizon, Mathilde
AU - Bruel, Ange-Line
AU - Philippe, Christophe
AU - Grant, Patricia E.
AU - Wojcik, Monica H.
AU - Stoler, Joan
AU - Genetti, Casie A.
AU - van Dooren, Marieke F.
AU - Maas, Saskia M.
AU - Alders, Marielle
AU - Faivre, Laurence
AU - Sorlin, Arthur
AU - Yoon, Grace
AU - Yalcin, Binnaz
AU - Agrawal, Pankaj B.
PY - 2020/12/3
Y1 - 2020/12/3
N2 - 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.
AB - 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.
KW - JMJD2B
KW - KDM4B
KW - agenesis of the corpus callosum
KW - dysmorphic hippocampi
KW - global developmental delay
KW - heterozygous variant
KW - intellectual disability
KW - neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85097310504&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2020.11.001
DO - https://doi.org/10.1016/j.ajhg.2020.11.001
M3 - Article
C2 - 33232677
SN - 0002-9297
VL - 107
SP - 1170
EP - 1177
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -