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
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."
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
"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
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.
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
"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.