Molecular convergence of neurodevelopmental disorders.

TitleMolecular convergence of neurodevelopmental disorders.
Publication TypeJournal Article
Year of Publication2014
AuthorsChen ES, Gigek CO, Rosenfeld JA, Diallo AB, Maussion G, Chen GG, Vaillancourt K, Lopez JP, Crapper L, Poujol R, Shaffer LG, Bourque G, Ernst C
JournalAm J Hum Genet
Date Published2014 Nov 6
KeywordsBasic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cells, Cultured, Chromatin Immunoprecipitation, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 9, Craniofacial Abnormalities, DNA Methylation, Evolution, Molecular, Gene Knockdown Techniques, Haploinsufficiency, Heart Defects, Congenital, Histone-Lysine N-Methyltransferase, Humans, Immunohistochemistry, Intellectual Disability, MicroRNAs, Microscopy, Confocal, Neural Stem Cells, Real-Time Polymerase Chain Reaction, Sequence Analysis, RNA, Transcription Factors

Neurodevelopmental disorders (NDDs) are caused by mutations in diverse genes involved in different cellular functions, although there can be crosstalk, or convergence, between molecular pathways affected by different NDDs. To assess molecular convergence, we generated human neural progenitor cell models of 9q34 deletion syndrome, caused by haploinsufficiency of EHMT1, and 18q21 deletion syndrome, caused by haploinsufficiency of TCF4. Using next-generation RNA sequencing, methylation sequencing, chromatin immunoprecipitation sequencing, and whole-genome miRNA analysis, we identified several levels of convergence. We found mRNA and miRNA expression patterns that were more characteristic of differentiating cells than of proliferating cells, and we identified CpG clusters that had similar methylation states in both models of reduced gene dosage. There was significant overlap of gene targets of TCF4 and EHMT1, whereby 8.3% of TCF4 gene targets and 4.2% of EHMT1 gene targets were identical. These data suggest that 18q21 and 9q34 deletion syndromes show significant molecular convergence but distinct expression and methylation profiles. Common intersection points might highlight the most salient features of disease and provide avenues for similar treatments for NDDs caused by different genetic mutations.

Alternate JournalAm. J. Hum. Genet.
PubMed ID25307298
PubMed Central IDPMC4225591