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Am J Hum Genet. 2015 May 7;96(5):784-96. doi: 10.1016/j.ajhg.2015.04.002. Epub 2015 Apr 30.

A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology.

Author information

1
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland.
2
Center for Human Disease Modeling and Department of Cell Biology, Duke University, Durham, NC 27710, USA.
3
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Estonian Genome Center, University of Tartu, Riia 23B, 51010 Tartu, Estonia.
4
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
5
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
6
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
7
Service of Medical Genetics, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.
8
Department of Medical Genetics, University Medical Center Utrecht, Lundlaan 6, 3508 AB Utrecht, the Netherlands.
9
Institut de Génétique Médicale, CHRU de Lille - Hôpital Jeanne de Flandre, Avenue Eugène Avinée, 59037 Lille, France.
10
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Genetics and Neurology, Harvard Medical School, Boston, MA 02114, USA.
11
Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland; Service of Medical Genetics, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland; Department of Medical Genetics, University of Lausanne, 1011 Lausanne, Switzerland.
12
Center for Human Disease Modeling and Department of Cell Biology, Duke University, Durham, NC 27710, USA. Electronic address: katsanis@cellbio.duke.edu.
13
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: alexandre.reymond@unil.ch.

Abstract

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

PMID:
25937446
PMCID:
PMC4570289
DOI:
10.1016/j.ajhg.2015.04.002
[Indexed for MEDLINE]
Free PMC Article

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