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CHARGE and Kabuki syndromes: Gene-specific DNA methylation signatures

ABSTRACT: Epigenetic dysregulation has emerged as mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7LOF) and lysine (K) methyltransferase 2D (KMT2DLOF), respectively. We expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these conditions, as well as specific target genes for each. Genome-wide DNAm profiles in individuals with CHARGE and Kabuki syndromes with CHD7LOF or KMT2DLOF identified distinct sets of DNAm differences in each of the disorders, which were used to generate two unique, highly specific and sensitive DNAm signatures. These DNAm signatures were able to differentiate pathogenic mutations in these two genes from controls and from each other. Analysis of each gene-specific DNAm signature identified common gene targets which could account for some of the clinical overlap in these syndromes, as well as distinct gene targets. Our findings demonstrate how characterization of the epigenome can contribute to our understanding of disease pathophysiology for epigenetic disorders, paving the way for explorations of novel therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97362 | GEO | 2017/05/03

SECONDARY ACCESSION(S): PRJNA381502

REPOSITORIES: GEO

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