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.
Original language | English (US) |
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Pages (from-to) | 565-578 |
Number of pages | 14 |
Journal | American journal of human genetics |
Volume | 95 |
Issue number | 5 |
DOIs | |
State | Published - 2014 |
Funding
We thank the families for their participation in the study. This work was supported in part by US National Institute of Neurological Disorders and Stroke (NINDS) grants R01 NS058529 to J.R.L. and 5K08NS062711 to M.B.R.; US National Human Genome Research Institute/National Heart Blood and Lung Institute (NHGRI/NHBLI) grant U54HG006542 to J.R.L.; by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), a Young Investigator fellowship from the Science without Borders Program grant 402520/2012-2 to C.M.B.C.; and a grant from the Simons Foundation to N.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NHGRI, NIH, or CNPq. J.R.L. holds stock ownership in 23andMe, Inc., and is a coinventor on multiple United States and European patents related to molecular diagnostics. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered in the Medical Genetics Laboratories.
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)