Genetics of Heart Defects

Proof that Three Distinct Cardiac Defects Share an Origin

Like a windstorm that leaves one household without power, another with downed trees and a third with roof damage, scientists are finding that congenital heart conditions can have differing effects, yet stem from a common biological event. The Mystery of Left-Heart Malformations Congenital cardiovascular malformations are among the most common birth defects in the United States. One group of heart defects known as left ventricular outflow tract obstruction (LVOTO) malformations arise from obstruction of blood flow through the developing left ventricle and aorta.  These malformations include aortic valve stenosis, coarctation of the aorta and hypoplastic left heart syndrome.  Without major surgery during the first few days of life, many newborns with an LVOT malformation, especially those with hypoplastic left heart syndrome, will die.

Presumably, these defects arise when the inner lining of the heart or aorta develops improperly, but the basic, disease-causing mechanisms remain unclear.  Scientists believe they are likely a complex mix of defects in one or more genes, chromosomal abnormalities and possibly environmental exposures.

Despite the myriad of mutations that could be responsible for each of the LVOT malformations, faculty members at The Research Institute are discovering that the most telling explanation of disease development could be revealed by studying the disorders together as a group. 

“Clinicians traditionally thought of these heart defects as separate entities,” said Kim L. McBride, MD, principal investigator in the Center for Molecular and Human Genetics at The Research Institute.  “More recent views have grouped them together based on findings from cardiac developmental biology, observations of clustering in families, and our own previous work on inheritance analysis.”

Linked by a Molecular Mechanism
Research conducted by Dr. McBride and colleagues reveals, for the first time, a common molecular mechanism for aortic valve stenosis, coarctation of the aorta and hypoplastic left heart syndrome. Although all three conditions involve the left side of the heart, a molecular similarity between the three defects had not yet been identified.

During the study, which appears in Human Molecular Genetics, 91 patients with LVOT malformations had their DNA screened for mutations in NOTCH1, a gene that has been linked to an aortic valve condition and that is part of a signaling pathway involved in multiple developmental processes. These patients’ DNA was then compared to that of 216 people without LVOT malformations.  Results showed that NOTCH1 gene mutations are present in some individuals with aortic valve stenosis, coarctation of the aorta and hypoplastic left heart syndrome.

Collaborative research between Kim L. McBride, MD, and Susan Cole, PhD, are revealing new information about how some heart defects develop.

With the help of Dr. Susan Cole, Assistant Professor in the College of Biological Sciences at The Ohio State University, several of these mutations were shown to affect Notch pathway signaling in the cell.  This suggests that Notch signaling plays a vital role during cardiovascular development and relatively minor changes may promote LVOT defects.  “These findings support our previous idea that these defects may share a common developmental pathogenesis,” said Dr. McBride.  “They also emphasize the hereditary nature of these defects and explain why one can find individuals in the same family with different forms of LVOT malformations.”

Searching for a Genetic Link
Since Dr. McBride’s group has established that there is a strong and complex genetic component to LVOT malformations, their focus is now to pinpoint the genes behind the disorders. Using a variety of study designs for gene mapping, the team is analyzing the pattern of inheritance of selected genes in signaling pathways important in cardiac development. 

These data provide the initial phase for gene identification of these LVOT malformations, a basic-science discovery that could be translated into improved patient care.  “Identifying a specific gene also now holds hope for eventually providing better risk counseling for families,” said Dr. McBride.

Scientific Translation through Clinical Collaboration
In order to progress toward gene discovery, Dr. McBride’s team must maintain the clinical collaborations that have been so vital in their present research.  While Dr. McBride’s team utilizes animal models during their studies, no existing animal models precisely mimic LVOT malformations.  This is why much of their research directly involves real-life patient samples. 

The complex nature of this translational work necessitates close collaborations with a variety of skilled people including a genetic counselor that recruits patients and families and collects detailed medical and family histories and blood for lab studies.  This information then becomes part of an extensive clinical database that serves as a repository for scientific study.  

Dr. McBride also collaborates with clinical faculty at Nationwide Children’s including surgeons who provide heart tissue samples donated by patients during cardiac surgery. “It would be impossible to conduct this research without the teamwork of our on-site surgeons because the tissue samples are too fragile to be shipped from one location to another,” said Dr. McBride.  “It also helps that we are able to collaborate with doctors who are leaders in the treatment of hypoplastic left heart syndrome.”

Ultimately, the genetic information obtained by Dr. McBride and his colleagues may result in genetic tests to identify at risk pregnancies early and help develop unique treatments and improved surgical techniques. 

“Although we are at the beginning of our hunt for the causes of these devastating heart malformations, we now have a better view of our target,” said Dr. McBride.  “Knowing that LVOT malformations share a common molecular mechanism is a big step forward, as it allows us to more effectively focus our efforts, provides the first clues to the underlying pathogenesis, and hopefully will allow improved genetic counseling for affected families.”

Further reading:
McBride KL, Riley MF, Zender GA, Fitzgerald-Butt SM, Towbin JA, Belmont JW, Cole SE. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Hum Mol Genet. 2008 Sep 15;17(18):2886-93.

McBride KL, Zender GA, Fitzgerald-Butt SM, Koehler D, Menesses-Diaz A, Fernbach S, Lee K, Towbin JA, Leal S, Belmont JW. Linkage analysis of left ventricular outflow tract malformations (aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome). Eur J Hum Genet. 2009 Jan 14. [Epub ahead of print]