The Practitioner's Perspective: The Genetic Link


We’re excited to bring you the following post from Paul Grossfeld, M.D., Associate Clinical Professor at UCSD School of Medicine and Attending Pediatric Cardiologist at Rady Children’s Hospital in San Diego. Dr. Grossfeld spent many hours caring for one of our own Sisters by Heart warriors, Travis DiCarlo, and subsequently spent time discussing his research with Travis’ parents, Roger and Nicole. Dr. Grossfeld’s research lab is working towards identifying the specific genetic causes of congenital heart defects in order to improve therapies and ultimately lead to prevention. Dr. Grossfeld’s lab is 50% funded by the Children’s Heart Foundation with the remaining funds coming from private fundraising efforts. It is our hope that funding for promising research, such as Dr. Grossfeld’s, improves drastically to increase awareness for CHD and the countless lives they effect.

Thank you so much Dr. Grossfeld for sharing your research with us!

Congenital heart defects are the most common type of birth defect, affecting almost 1% of all newborn infants. Hypoplastic left heart syndrome (HLHS) accounts for a small percentage of all heart defects, but remains one of the most common causes of death in infants with congenital heart disease. Although most cases of HLHS and other heart defects are due to a genetic cause, a specific disease-causing gene mutation is only known in about 10% of patients. Clearly, identifying the specific genetic causes of congenital heart defects will improve therapies and ultimately lead to prevention.

We have embarked on a multidisciplinary approach involving human genetics and genetically engineered animal models to identify genes for congenital heart defects, including HLHS. The first approach has focused on a rare chromosomal disorder called Jacobsen syndrome (11q-), caused by deletions in the 11th human chromosome. These patients have the highest frequency of HLHS of any known human genetic disorder, as well as many of the most common congenital heart defects that occur in the general population. The second approach entails studying other chromosomal disorders associated with congenital heart disease. Specifically, with recent technological advances, patients with congenital heart defects can be analyzed to identify microscopic losses or gains of chromosomal material that contain genes that cause congenital heart defects. 

We have recently identified several new chromosomal disorders that likely harbor previously unidentified disease-causing genes for congenital heart defects. Lastly, with the amazing advances in DNA sequencing technologies, it is now feasible to perform direct DNA sequencing on the entire genome (i.e., of all ~30,000 genes) to identify a putative disease-causing mutation. Taken together, these three approaches are enabling us to identify numerous new “candidate disease-causing genes.”

Due to obvious limitations in human genetic studies, we have utilized genetically engineered animal models to study the function of candidate genes in heart development, and to establish causality for specific heart defects. Towards that end, we have demonstrated that deletion of a single gene in the mouse that is deleted in Jacobsen syndrome causes heart defects, including a hypoplastic left ventricle and ventricular septal defects. We are also using simpler organisms including zebrafish and chicks to understand further the functions of these genes. These studies allow us to identify the specific cellular lineages in cardiac development, which could lead to new strategies for the prevention of congenital heart defects.

We are also embarking on a recently developed technology that allows human skin cells to be “reprogrammed” into developing heart cells. As described above, specific lineages in which the causative gene is known to function can then be studied to characterize the mechanism by which absence of the gene causes heart defects, so-called “disease in a dish”. This extraordinary technology will eventually lead to the identification of putative drugs that could potentially preserve the function of these cellular lineages during heart development, thereby preventing some types of congenital heart defects.

Click here for a list of Dr. Grossfeld’s publications.

To support Dr. Grossfeld’s research, please mail checks to:
UC San Diego
Health Sciences Development
200 West Arbor Dr. #8982
San Diego, CA 92103-8982
Attention: Shawna Fallon

Payment can be made to: “UC Regents #42364

To make a donation over the phone, please call 619-543-3499.

94% of all donations go DIRECTLY to support Dr. Grossfeld’s research!!!