Author | Fonseca, Claudia Marcia Benedetto de Carvalho | |
Author | Vasanth, Shivakumar | |
Author | Shinawi, Marwan | |
Author | Russell, Chad | |
Author | Ramocki, Melissa B. | |
Author | Brown, Chester W. | |
Author | Graakjaer, Jesper | |
Author | Bine Skytte, Anne | |
Author | Morgante, Angela Maria Vianna | |
Author | Krepischi, Ana Cristina Victorino | |
Author | Patel, Gayle S. | |
Author | Immken, LaDonna | |
Author | Aleck, Kyrieckos | |
Author | Lim, Cynthia | |
Author | Cheung, Sau Wai | |
Author | Rosenberg, Carla | |
Author | Katsanis, Nicholas | |
Access date | 2015-07-23T16:05:33Z | |
Available date | 2015-07-23T16:05:33Z | |
Document date | 2014 | |
Citation | CARVALHO, Claudia Marcia Benedetto et al. Dosage Changes of a Segment at 17p13.1 Lead to Intellectual Disability and Microcephaly as a Result of Complex Genetic Interaction of Multiple Genes. Am J Hum Genet. 2014 Nov 6;95(5):565-78. | pt_BR |
ISSN | 0002-9297 | |
URI | https://www.arca.fiocruz.br/handle/icict/11402 | |
Language | eng | pt_BR |
Publisher | Elsevier Inc | pt_BR |
Rights | open access | pt_BR |
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 | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.ajhg.2014.10.006 | |
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. | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA /Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, Brazil | pt_BR |
Affilliation | Duke University. Center for Human Disease Modeling.Durham, NC, USA | pt_BR |
Affilliation | Washington University . Division of Genetics and Genomic Medicine. Department of Pediatrics. St Louis, MO, USA | pt_BR |
Affilliation | Duke University. Center for Human Disease Modeling.Durham, NC, USA | pt_BR |
Affilliation | Baylor College of Medicine. Department of Pediatrics. Houston, TX, USA/ Texas Children’s Hospital. Houston, TX , USA | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA /Baylor College of Medicine. Department of Pediatrics. Houston, TX, USA/ Texas Children’s Hospital. Houston, TX , USA | pt_BR |
Affilliation | Vejle Hospital. Clinical Genetics Department. Vejle, Denmark | pt_BR |
Affilliation | Vejle Hospital. Clinical Genetics Department. Vejle, Denmark | pt_BR |
Affilliation | Universidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, Brazil | pt_BR |
Affilliation | Universidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, Brazil | pt_BR |
Affilliation | Texas Oncology. Austin, TX, USA | pt_BR |
Affilliation | Specially for Children. Austin, TX, USA | pt_BR |
Affilliation | Phoenix Children’s Hospital. Phoenix, AZ, USA | pt_BR |
Affilliation | Phoenix Children’s Hospital. Phoenix, AZ, USA | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA | pt_BR |
Affilliation | Universidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, Brazil | pt_BR |
Affilliation | Duke University. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
Subject | Abnormalities, Multiple/genetics | pt_BR |
Subject | Chromosomes, Human, Pair 17/genetics | pt_BR |
Subject | Molecular Sequence Data | pt_BR |
Subject | Sequence Analysis, DNA | pt_BR |