Summaries of Research Results

CANOES: Detecting rare copy number variants from whole exome sequencing data. Backenroth D, Homsy J, Murillo LR, Glessner J, Lin E, et al. Nucleic Acids Research 2014; 42(12):e97

Our paper "CANOES: Detecting rare copy number variants from whole exome sequencing data" took advantage of the unique genetic resource developed by the PCGC to develop a method to detect a specific kind of genetic anomaly, the rare copy number variant. In this kind of anomaly, which has been shown to be an important contributor to disease, a piece of genetic material is deleted or duplicated, resulting in a child that has more or fewer copies of a portion of the genome than it would in the absence of the anomaly. We developed a method to detect this kind of anomaly from the exome sequencing data generated by the PCGC. The PCGC data was ideal for our purposes, since both parents and affected children were sequenced, enabling us to carefully check our method's accuracy.


De novo mutations in histone-modifying genes in congenital heart disease. Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, et al. Nature 498, 220–223 (13 June 2013)

Congenital heart disease (CHD) is the most common cause of non-infectious death in newborns, affecting 0.8% of all live births. Our study focused on understanding the genetic underpinnings behind CHD. We recognized that many CHD cases occurred sporadically lacking a family history of disease. As a child shares ~50% of their DNA with each parent, we leveraged new sequencing technology to detect genetic mutations that were not transmitted from parent to the child, but rather found new or de novo within the affected child. We found that these de novo mutations contribute to approximately 10% of severe CHD, those cases that require surgery within the first year of life.  As proof of our method, we found a significant number of de novo mutations in previously defined CHD genes. We additionally identified a number of novel genes associated with CHD. In particular, there was a striking overrepresentation of de novo mutations in chromatin-modifying genes, a set of genes crucial for the development of our body and organs. It was also first found that there is a significant overlap of mutated genes between CHD and other neurodevelopmental deficits, such as autism among others. These findings suggest an overlapping genetic etiology behind these two developmental disorders. These observations, and continued and tireless ongoing work to identify further genes underlying CHD, will be important for patient care and genetic counseling.


Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Glessner JT, Bick AG, Ito K, Homsy JG, et al. Circ Res. 2014 Oct 24;115(10):884-96.

Congenital heart disease is a malformation of the heart at birth, which disrupts the intricate balance of oxygenated and deoxygenated blood, which needs to circulate throughout the body. Various technologies and models can survey genetics of congenital heart disease. Here, we show the utility of two complementary technologies to assess the genome, single nucleotide polymorphism microarray which looks at bases found to differ between individuals and exome sequencing which looks at all bases in gene exons which directly encode functional products. De novo copy number variants, losses or gains of genetic segments in the child affected with congenital heart disease but not the parents, is the clearest causality genetic model and the one focused upon here. The presence of these genetic events exclusively in the affected child was validated by an independent technology, digital droplet polymerase chain reaction.

We observed recurrent de novo copy number variants on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE, SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. In this way, we are able to see convergence of singular observations of de novo CNVs into biological pathways of function for heart development. We were able to narrow the definition of previously described large syndromic copy number variants showing ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions. By assessing the gene exons deeply and complementing that with the genomic backbone of the single nucleotide polymorphism microarray data, we were able to find important genetic markers which can flag early diagnostics and interventions in the future of possible congenital heart defect.