Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 95, Issue 5, Pages 565-578Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2014.10.006
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Funding
- US National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS058529, 5K08NS062711]
- US National Human Genome Research Institute/National Heart Blood and Lung Institute (NHGRI/NHBLI) [U54HG006542]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), a Young Investigator fellowship from the Science without Borders Program [402520/2012-2]
- Simons Foundation
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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.
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