0000000000187692
AUTHOR
Teresa Santiago-sim
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
AbstractWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene,SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carryingSATB1variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression…
Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects
International audience; 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 a…