Skip to main content
ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #294302
Title: Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities

Author
item LALANI, SEEMA - Children'S Nutrition Research Center (CNRC)
item SHAW, CHAD - Baylor College Of Medicine
item WANG, XUEQING - Children'S Nutrition Research Center (CNRC)
item PATEL, ANKITA - Baylor College Of Medicine
item PATTERSON, LANCE - Texas Children'S Hospital
item KOLODZIEJSKA, KATARZYNA - Baylor College Of Medicine
item SZAFRANSKI, PRZEMYSLAW - Baylor College Of Medicine
item OU, ZHISHUO - Baylor College Of Medicine
item TIAN, QI - Baylor College Of Medicine
item KANG, SUNG-HAE - Baylor College Of Medicine
item JINNAH, AMINA - Baylor College Of Medicine
item ALI, SOPHIA - University Of Texas
item MALIK, AAMIR - Aga Khan University
item HIXSON, PATRICIA - Baylor College Of Medicine
item POTOCKI, LORRAINE - Baylor College Of Medicine
item LUPSKI, JAMES - Baylor College Of Medicine
item STANKIEWICZ, PAWEL - Baylor College Of Medicine
item BACINO, CARLOS - Baylor College Of Medicine
item DAWSON, BRIAN - Baylor College Of Medicine
item BEAUDET, ARTHUR - Baylor College Of Medicine
item BORICHA, FATIMA - University Of Texas
item WHITTAKER, RUNAKO - St John Health System
item LI, CHUMEI - McMaster University
item WARE, STEPHANIE - Children'S Hospital - Cincinnati, Ohio
item CHEUNG, SAU - Baylor College Of Medicine
item PENNY, DANIEL - Texas Children'S Hospital
item JEFFRIES, JOHN - Children'S Hospital - Cincinnati, Ohio
item BELMONT, JOHN - Children'S Nutrition Research Center (CNRC)

Submitted to: European Journal of Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/13/2012
Publication Date: 2/1/2013
Citation: Lalani, S.R., Shaw, C., Wang, X., Patel, A., Patterson, L.W., Kolodziejska, K., Szafranski, P., Ou, Z., Tian, Q., Kang, S.L., Jinnah, A., Ali, S., Malik, A., Hixson, P., Potocki, L., Lupski, J.R., Stankiewicz, P., Bacino, C.A., Dawson, B., Beaudet, A.L., Boricha, F.M., Whittaker, R., Li, C., Ware, S.M., Cheung, S.W., Penny, D.J., Jeffries, J.L., Belmont, J.W. 2013. Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. European Journal of Human Genetics. 21(2):173-181.

Interpretive Summary: Congenital heart defects are the leading cause of infant mortality attributable to birth defects in the U.S. Discovering the genetic loci that contribute to heart defects is an important first step to understanding how their occurrence can be reduced and the effects mitigated. In this study we evaluated the role of rare genomic abnormalities as potential causes of complex birth defects involving the heart. We studied children with a heart defect and at least one other major birth defect. We found 16 loci that were present in both a discovery and replication study. These loci are most likely the cause of the heart defects in these children. The study also allowed us to refine the intervals for several other loci that previously had been reported to cause heart defects. It is known that the risk of heart defects is increased in maternal obesity and diabetes. Many other studies have linked birth defects to maternal nutrition. Studies of genetic disorders, by identifying the required steps in heart development, help to identify which aspects of normal heart development are disturbed by nutritional imbalances.

Technical 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.