Affordable Access

deepdyve-link deepdyve-link
Publisher Website

Molecular convergence of neurodevelopmental disorders.

Authors
Type
Published Article
Journal
The American Journal of Human Genetics
1537-6605
Publisher
Elsevier
Publication Date
Volume
95
Issue
5
Pages
490–508
Identifiers
DOI: 10.1016/j.ajhg.2014.09.013
PMID: 25307298
Source
Medline
License
Unknown

Abstract

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.

Statistics

Seen <100 times