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Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

ABSTRACT: 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.

SUBMITTER: Duncan AR

PROVIDER: S-EPMC7820620 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

Duncan Anna R AR Vitobello Antonio A Collins Stephan C SC Vancollie Valerie E VE Lelliott Christopher J CJ Rodan Lance L Shi Jiahai J Seman Ann R AR Agolini Emanuele E Novelli Antonio A Prontera Paolo P Guillen Sacoto Maria J MJ Santiago-Sim Teresa T Trimouille Aurélien A Goizet Cyril C Nizon Mathilde M Bruel Ange-Line AL Philippe Christophe C Grant Patricia E PE Wojcik Monica H MH Stoler Joan J Genetti Casie A CA van Dooren Marieke F MF Maas Saskia M SM Alders Marielle M Faivre Laurence L Sorlin Arthur A Yoon Grace G Yalcin Binnaz B Agrawal Pankaj B PB

American journal of human genetics 20201123 6

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 pr ...[more]

PMID: 33232677

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Project description:ImportanceAlthough the effects of lead (Pb) exposure on neurocognition in children have been confirmed, the individual associations of prenatal Pb exposure and its interaction with genetic factors on cognitive developmental delay (CDD) in children remain unclear.ObjectiveTo investigate the association of prenatal Pb exposure and its interaction with genetic factors with CDD risk.Design, setting, and participantsWomen in Wuhan, China, who had an expected delivery date between March 2014 and December 2017, were recruited for this prospective cohort study. Children were assessed for cognitive development at approximately 2 years of age (March 2016 to December 2019). Maternal venous blood, cord blood, and venous blood from children were collected in a longitudinal follow-up. Data analysis was performed from March 2022 to February 2023.ExposurePrenatal Pb exposure, and genetic risk for cognitive ability evaluated by polygenic risk score constructed with 58 genetic variations.Main outcomes and measuresCognitive developmental delay of children aged approximately 2 years was assessed using the Chinese revision of the Bayley Scale of Infant Development. A series of multivariable logistic regressions was estimated to determine associations between prenatal Pb exposure and CDD among children with various genetic backgrounds, adjusting for confounding variables.ResultsThis analysis included 2361 eligible mother-child pairs (1240 boys [52.5%] and 1121 girls [47.5%]; mean [SD] ages of mothers and children, 28.9 [3.6] years and 24.8 [1.0] months, respectively), with 292 children (12.4%) having CDD. Higher maternal Pb levels were significantly associated with increased risk of CDD (highest vs lowest tertile: odds ratio, 1.55; 95% CI, 1.13-2.13), adjusting for demographic confounders. The association of CDD with maternal Pb levels was more evident among children with higher genetic risk (highest vs lowest tertile: odds ratio, 2.59; 95% CI, 1.48-4.55), adjusting for demographic confounders.Conclusions and relevanceIn this cohort study, prenatal Pb exposure was associated with an increased risk of CDD in children, especially in those with a high genetic risk. These findings suggest that prenatal Pb exposure and genetic background may jointly contribute to an increased risk of CDD for children and indicate the possibility for an integrated strategy to assess CDD risk and improve children's cognitive ability.

Dataset Information

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

Publications

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

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