Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities

Seema R. Lalani, Chad Shaw, Xueqing Wang, Ankita Patel, Lance W. Patterson, Katarzyna Kolodziejska, Przemyslaw Szafranski, Zhishuo Ou, Qi Tian, Sung Hae L. Kang, Amina Jinnah, Sophia Ali, Aamir Malik, Patricia Hixson, Lorraine Potocki, James R. Lupski, Pawel Stankiewicz, Carlos A. Bacino, Brian Dawson, Arthur L. BeaudetFatima M. Boricha, Runako Whittaker, Chumei Li, Stephanie M. Ware, Sau Wai Cheung, Daniel J. Penny, John Lynn Jefferies, John W. Belmont

Research output: Contribution to journalArticle

37 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)173-181
Number of pages9
JournalEuropean Journal of Human Genetics
Issue number2
StatePublished - Feb 1 2013
Externally publishedYes


  • 16q24.3 microdeletion
  • Rare copy number variations
  • cardiovascular malformations (CVMs)
  • extracardiac anomalies (ECAs)
  • protein-interaction network

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Lalani, S. R., Shaw, C., Wang, X., Patel, A., Patterson, L. W., Kolodziejska, K., Szafranski, P., Ou, Z., Tian, Q., Kang, S. H. L., Jinnah, A., Ali, S., Malik, A., Hixson, P., Potocki, L., Lupski, J. R., Stankiewicz, P., Bacino, C. A., Dawson, B., ... Belmont, J. W. (2013). Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. European Journal of Human Genetics, 21(2), 173-181. https://doi.org/10.1038/ejhg.2012.155