title: Characterization of molecular and cellular phenotypes associated with a heterozygousCNTNAP2deletion using patient-derived hiPSC neural cells.
abstract: Neurodevelopmental disorders, such as autism spectrum disorders (ASD) and schizophrenia (SZ), are complex disorders with a high degree of heritability. Genetic studies have identified several candidate genes associated with these disorders, including contactin-associated protein-like 2 (CNTNAP2). Traditionally, in animal models orin vitro, the function ofCNTNAP2has been studied by genetic deletion or transcriptional knockdown, which reduce the expression of the entire gene; however, it remains unclear whether the mutations identified in clinical settings are sufficient to alterCNTNAP2expression in human neurons. Here, using human induced pluripotent stem cells (hiPSCs) derived from two individuals with a large (289kb) and heterozygous deletion inCNTNAP2(affecting exons 14-15) and discordant clinical outcomes, we have characterizedCNTNAP2expression patterns in hiPSC neural progenitor cells (NPCs), two independent populations of hiPSC-derived neurons and hiPSC-derived oligodendrocyte precursor cells (OPCs). First, we observed exon-specific changes inCNTNAP2expression in both carriers; although the expression of exons 14-15 is significantly decreased, the expression of other exons is upregulated. Second, we observed significant differences in patterns of allele-specific expression inCNTNAP2carriers that were consistent with clinical outcome. Third, we observed a robust neural migration phenotype that correlated with diagnosis and exon- and allele-specificCNTNAP2expression patterns, but not with genotype. In all, our data highlight the importance of considering the nature, location and regulation of mutated alleles when attempting to connect GWAS studies to gene function.
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029.
authors.forename: Inkyu S
authors.initials: IS
authors.lastname: Lee
authors.affiliation: Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, TX 77030.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: The New York Stem Cell Foundation, New York, NY 10032, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Douvaras
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029.
authors.forename: Seok-Man
authors.initials: SM
authors.lastname: Ho
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029.
authors.forename: Brigham J
authors.initials: BJ
authors.lastname: Hartley
authors.affiliation: Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, TX 77030.
authors.forename: Luciana W
authors.initials: LW
authors.lastname: Zuccherato
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Ladran
authors.affiliation: Internal Medicine Department, McLean Hospital, Belmont, Massachusetts 02478, USA.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Siegel
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724.
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Malhotra
authors.affiliation: University of California San Diego, Department of Psychiatry and Department of Cellular and Molecular Medicine, University Of California, San Diego, La Jolla, CA 92093.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
authors.affiliation: Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Rapoport
authors.affiliation: The New York Stem Cell Foundation, New York, NY 10032, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fossati
authors.affiliation: Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, TX 77030; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Baylor College of Medicine, Department of Pediatrics, Houston, Texas 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts 02478, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Levy
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Brennand