title: Loss of δ-catenin function in severe autism.
abstract: Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
authors: 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA.
authors: Tychele N
authors: TN
authors: Turner
authors: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: Kamal
authors: K
authors: Sharma
authors: Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA.
authors: Edwin C
authors: EC
authors: Oh
authors: Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA.
authors: Yangfan P
authors: YP
authors: Liu
authors: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Ryan L
authors: RL
authors: Collins
authors: 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA.
authors: Maria X
authors: MX
authors: Sosa
authors: 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA.
authors: Dallas R
authors: DR
authors: Auer
authors: 1] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA.
authors: Harrison
authors: H
authors: Brand
authors: 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
authors: Stephan J
authors: SJ
authors: Sanders
authors: 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, Yale University, New Haven, Connecticut 06511, USA.
authors: Daniel
authors: D
authors: Moreno-De-Luca
authors: 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA.
authors: Vasyl
authors: V
authors: Pihur
authors: Leidos Biomedical Research, Inc., Frederick, Maryland 21702, USA.
authors: Teri
authors: T
authors: Plona
authors: Leidos Biomedical Research, Inc., Frederick, Maryland 21702, USA.
authors: Kristen
authors: K
authors: Pike
authors: Leidos Biomedical Research, Inc., Frederick, Maryland 21702, USA.
authors: Daniel R
authors: DR
authors: Soppet
authors: National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
authors: Michael W
authors: MW
authors: Smith
authors: Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Sau Wai
authors: SW
authors: Cheung
authors: 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Autism &Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania 17837, USA.
authors: Christa Lese
authors: CL
authors: Martin
authors: 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
authors: Matthew W
authors: MW
authors: State
authors: 1] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA.
authors: Michael E
authors: ME
authors: Talkowski
authors: University of Illinois at Chicago, Chicago, Illinois 60608, USA.
authors: Edwin
authors: E
authors: Cook
authors: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: Richard
authors: R
authors: Huganir
authors: Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA.
authors: Nicholas
authors: N
authors: Katsanis
authors: 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA.
authors: Aravinda
authors: A
authors: Chakravarti
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism*; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D051177:Catenins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008957:Models, Genetic; D020412:Multifactorial Inheritance / Q000235:genetics; D020125:Mutation, Missense; D009415:Nerve Net; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D012727:Sex Characteristics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D002843:Chromatin; D000095002:Delta Catenin