title: Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes.
abstract: The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Centro de Pesquisas René Rachou - FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Vasanth
authors.affiliation: Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University in St Louis, St Louis, MO 63110-1093, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Russell
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Ramocki
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Chester W
authors.initials: CW
authors.lastname: Brown
authors.affiliation: Clinical Genetics Department, Vejle Hospital, Vejle 7100, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Graakjaer
authors.affiliation: Clinical Genetics Department, Vejle Hospital, Vejle 7100, Denmark.
authors.forename: Anne-Bine
authors.initials: AB
authors.lastname: Skytte
authors.affiliation: Department of Genetics & Evolutionary Biology, Biosciences Institute, University of São Paulo, São Paulo, SP 05508-090, Brazil.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Vianna-Morgante
authors.affiliation: Department of Genetics & Evolutionary Biology, Biosciences Institute, University of São Paulo, São Paulo, SP 05508-090, Brazil.
authors.forename: Ana C V
authors.initials: AC
authors.lastname: Krepischi
authors.affiliation: Texas Oncology, Austin, TX 78731, USA.
authors.forename: Gayle S
authors.initials: GS
authors.lastname: Patel
authors.affiliation: Specially for Children, Austin, TX 78723, USA.
authors.forename: LaDonna
authors.initials: L
authors.lastname: Immken
authors.affiliation: Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
authors.forename: Kyrieckos
authors.initials: K
authors.lastname: Aleck
authors.affiliation: Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lim
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Genetics & Evolutionary Biology, Biosciences Institute, University of São Paulo, São Paulo, SP 05508-090, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Rosenberg
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA. Electronic address: nicholas.katsanis@dm.duke.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D037263:Asialoglycoprotein Receptor / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D000072261:Dishevelled Proteins; D005434:Flow Cytometry; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008607:Intellectual Disability / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D058496:Smith-Magenis Syndrome; D013577:Syndrome; D015027:Zebrafish
chemical_list: C546927:ASGR1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D037263:Asialoglycoprotein Receptor; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C116741:GABARAP protein, human; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D044942:Acyl-CoA Dehydrogenase, Long-Chain; C467805:ACADVL protein, human