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Am J Hum Genet. 2014 Nov 6;95(5):565-78. doi: 10.1016/j.ajhg.2014.10.006. Epub 2014 Nov 6.

Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes.

Author information

1
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.
2
Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA.
3
Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University in St Louis, St Louis, MO 63110-1093, USA.
4
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
5
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.
6
Clinical Genetics Department, Vejle Hospital, Vejle 7100, Denmark.
7
Department of Genetics & Evolutionary Biology, Biosciences Institute, University of São Paulo, São Paulo, SP 05508-090, Brazil.
8
Texas Oncology, Austin, TX 78731, USA.
9
Specially for Children, Austin, TX 78723, USA.
10
Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
11
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
12
Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA. Electronic address: nicholas.katsanis@dm.duke.edu.
13
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.

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.

PMID:
25439725
PMCID:
PMC4225592
DOI:
10.1016/j.ajhg.2014.10.006
[Indexed for MEDLINE]
Free PMC Article

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