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News and Features Unraveling the Genetics of Congenital Heart Disease

As we learn more about the human genome, our understanding of cardiac disease processes and treatment continues to change.

Partnering with our internationally known Division of Clinical Pharmacology and Therapeutic Innovation, the hospital's unique Center for Genomic Medicine, and a robust Clinical Genetics program, Children's Mercy physicians and researchers are helping to advance the understanding of genetic causes of cardiovascular disease and how to utilize that knowledge to better treat patients.

Rapid Diagnosis of Disease

Researchers at the Children's Mercy Center for Genomic Medicine made international headlines recently with a breakthrough that provides rapid (50 hours versus weeks) whole genome sequencing for the diagnosis of genetic diseases. Already this technique has helped identify a novel, recessive gene for viscero-arterial heterotaxy. Such techniques have the potential to revolutionize our diagnostic capabilities in a manner previously unmatched for speed and precision.

"By shortening the time-to-diagnosis, we may markedly reduce the number of other tests performed and reduce delays to a diagnosis," says Stephen Kingsmore, M.B. Ch.B., D.Sc., FRCPath, Director of the Center for Pediatric Genomic Medicine at Children's Mercy. "Reaching an accurate diagnosis quickly can help to shorten hospitalization and reduce costs and stress for families."

Improving Treatment Effectiveness

Dyslipidemia is a major health concern not only for patients at Children's Mercy, but for the whole country. Statins, the most common class of drugs used to treat dyslipidemia in children and adults, hasn't really been tested in the developing child.

Jon Wagner, DO, a fellow in Cardiology and Clinical Pharmacology, and Steve Leeder, PharmD, PhD, Division Director of Clinical Pharmacology and Innovative Therapeutics, are looking at the liver specific protein transporter, OATP1B1,which is the major transporter of statins from the blood to the liver (statins' site of action), to better understand how children's bodies distribute statins in the body.

"Different types of polymorphisms or genetic variations in the genes for this transporter can affect how well the liver takes up medication. There is an exorbitant amount of information on how genetic variation of the transporters affects statin distribution in the body and how they can affect a clinical response in adults," says Dr. Wagner. "What we don't know is whether these polymorphisms in children affect the overall statin disposition or response to the drug in a growing child. This is something that has never been looked at extensively in children and adolescents."

Currently, biospecimens are being collected to perform a genetic analysis specifically for SLCO1B1 and other genes involved with statin disposition. The overall goal is to establish the role of not only genetic variation, but also age and development on the dose-exposure-response relationship for statins in children.

"Children undergo a lot of developmental changes or ontogeny, and we know with development, a lot of these drug transporters, drug metabolizing enzymes, do change either through gain of function or loss of function.

That's why this is of the utmost importance to look at," says Dr. Wagner.

Cardiac Genetics

The Children's Mercy Cardiovascular Genetics Clinic, staffed by cardiologists, geneticists and genetic counselors, provides a coordinated, integrated approach for the diagnosis, care and genetic counseling for syndromic and inheritable systemic disorders which typically include significant cardiovascular manifestations. The clinic makes use of available gene testing to aid in the patient evaluation and counseling, and is also working with other researchers to develop additional testing methods.

"Over the last 20 years there has been a tremendous amount of information uncovered about the genetic causes of disorders such as DiGeorge, Williams, Noonan and Marfan syndromes. There has also been a great deal learned about the genetic etiology of certain cardiomyopathies and cardiac dysrhythmias. These discoveries are proving to be extremely useful in the clinical care of patients with these conditions. The next big area for the future expansion of pediatric clinical cardiovascular genetics will be the translation of the basic science investigations into the genetic causes of structural congenital heart disease," says Robert Ardinger, MD, Cardiovascular Genetics Clinic Director.

He continues, "Congenital heart defects such as septal defect, valve abnormalities or vessel location, frequently occur as isolated problems, not obviously associated with other malformations or syndromes. There appear to be strong genetic influences to the cause of many of these disorders but they are not obviously inherited in a way we can easily understand." Dr. Ardinger, along with James O'Brien, MD, Co-Director of The Ward Family Heart Center at Children's Mercy, developed a DNA repository for all children receiving cardiovascular procedures at the hospital. Dr. O'Brien has used the repository in his ongoing investigation into the genetics of tetralogy of Fallot. Some of his work was recently published in the journal Cardiovascular Genetics.

"My hope is that we can use our general cardiology patients, the patients we see in the Cardiovascular Genetics Clinic, our DNA repository and our clinical genetics laboratories, along with the genomic tools Dr. Kingsmore is developing, to try to elucidate some of the causative gene mutations behind congenital structural heart disease," says Dr. Ardinger.

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