Abstract
Clinically significant cardiovascular malformations (CVMs) occur in 5–8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs.
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Acknowledgements
We thank the families for participating in the study. We thank Zhilian Xia for providing technical support. The support for this work was provided by the National Institutes of Health (RO1-HL091771) to JWB, Doris Duke Charitable Foundation and Gillson Longenbaugh Foundation to SRL and March of Dimes support (MOD: 1-FY10-401) to SRL and SMW. Pawel Stankiewicz was supported in part by Grant R13-0005-04/2008 from the Polish Ministry of Science and Higher Education.
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Multiple authors are based in the Department of Molecular and Human Genetics at Baylor College of Medicine, which derives revenue from molecular diagnostic testing (Medical Genetics Laboratories).
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Lalani, S., Shaw, C., Wang, X. et al. Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. Eur J Hum Genet 21, 173–181 (2013). https://doi.org/10.1038/ejhg.2012.155
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DOI: https://doi.org/10.1038/ejhg.2012.155
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