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Am J Hum Genet. 2014 Nov 6;95(5):490-508. doi: 10.1016/j.ajhg.2014.09.013. Epub 2014 Oct 9.

Molecular convergence of neurodevelopmental disorders.

Author information

1
Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
2
Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA 99207, USA.
3
McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada; Department of Human Genetics, McGill University, Montreal, QC H4H 1R3, Canada.
4
Paw Print Genetics, Genetic Veterinary Sciences Inc., Spokane, WA 99202, USA.
5
Department of Human Genetics, McGill University, Montreal, QC H4H 1R3, Canada; McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 0G1, Canada.
6
Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada; Department of Human Genetics, McGill University, Montreal, QC H4H 1R3, Canada. Electronic address: carl.ernst@mcgill.ca.

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.

PMID:
25307298
PMCID:
PMC4225591
DOI:
10.1016/j.ajhg.2014.09.013
[Indexed for MEDLINE]
Free PMC Article

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