title: Molecular convergence of neurodevelopmental disorders.
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.
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Carolina O
authors.initials: CO
authors.lastname: Gigek
authors.affiliation: Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA 99207, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Alpha B
authors.initials: AB
authors.lastname: Diallo
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Gilles
authors.initials: G
authors.lastname: Maussion
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Vaillancourt
authors.affiliation: 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.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Lopez
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Liam
authors.initials: L
authors.lastname: Crapper
authors.affiliation: Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada; McGill Group for Suicide Studies, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Poujol
authors.affiliation: Paw Print Genetics, Genetic Veterinary Sciences Inc., Spokane, WA 99202, USA.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H4H 1R3, Canada; McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 0G1, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: 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.
authors.forename: Carl
authors.initials: C
authors.lastname: Ernst
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D019175:DNA Methylation; D019143:Evolution, Molecular; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008607:Intellectual Disability / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D018613:Microscopy, Confocal; D058953:Neural Stem Cells; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D035683:MicroRNAs; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; C455847:EHMT1 protein, human; D011495:Histone-Lysine N-Methyltransferase