Johns Hopkins experts on the genetics of a potentially
lethal heart rhythm defect that runs in families and
targets young athletes report they have greatly narrowed
the hunt for the specific genetic mutations that contribute
to the problem.
Their new findings, described in the July issue of the
American Journal of Human Genetics, should increase
the accuracy of tests to identify those at risk for
arrhythmogenic right ventricular dysplasia, known as ARVD,
which is among the top causes of sudden cardiac death in
the young and fit.
In February, the same team linked one-third of ARVD
cases in their large database of patients to a dozen
abnormal changes in a gene called plakophilin 2, which
makes proteins involved in heart cell stickiness.
In the new study, confirming experiments elsewhere,
the Hopkins team found four mutations in another sticky
protein gene, Desmoglein 2, in five of 33 patients
"This gene is highly expressed in the heart, where
muscle tissue expands and contracts with the heartbeat,"
said senior study author and cardiac geneticist Daniel P.
Judge. "Our results confirm that altered genes in the
desmosomal cellular complex are responsible for ARVD. And
now that we know the genetic roots of this disease, we can
also create better blood tests for their proteins to
predict who is at risk for developing this condition."
ARVD is characterized by weakness in the desmosome, or
cell-to-cell binding structure. The inherited condition
leads to the buildup of excess fatty and scar tissue in the
heart's right ventricle, causing irregular beats and
— unless diagnosed and treated with drugs or
implanted defibrillators — triggering a fatal heart
Judge, an assistant professor at the School of
Medicine and its
Heart Institute, says DSG2 mutations appear to account
for at least 10 percent and possibly more of the estimated
25,000 deaths each year from ARVD.
The researchers, he said, expect a test for DSG2
mutations to be available to those with a family history of
the condition before the end of the year.
The same Hopkins team developed a blood test to screen
for PKP2 mutations. That test became available in May and
is currently the only one available for detecting those at
greater risk of the disease.
More than 400 people have been screened at Johns
Hopkins so far and, of these, two-thirds have had serious
enough forms of the condition to warrant implantation of a
defibrillator, an electrical device that corrects any
disturbances in the heart's rhythm.
The Hopkins researchers identified the DSG2 mutation
through genetic analysis of blood taken from 60 men and
women already diagnosed with ARVD. All were part of a
patient database created at Hopkins in 1998. The
researchers focused on cell adhesion proteins because they
had already been linked to Naxos syndrome, which produced
symptoms in the right ventricle similar to those documented
When scientists excluded their ARVD patients with PKP2
mutations, they were left with 33 who had no known genetic
explanation for their condition. Additional testing
revealed the four mutations in DSG2.
"We knew right away that we had found something very
significant," said lead author Mark Awad, a medical and
predoctoral sciences student at Hopkins. "The mutations
were confined to a highly functional part of the gene and
were highly conserved, meaning that evolution had not
drastically changed the genetic sequence over time —
the gene was kept the way it was because it was important
to the heart's normal function."
According to Awad, not everyone with a genetic
mutation develops ARVD. Further analysis of the condition's
genetic roots, he said, will help researchers to calculate
the precise increased risk from each mutation for
developing symptoms and dying. Previous research by the
Hopkins team showed that familial ARVD generally strikes
after puberty and its symptoms — dizziness, fatigue
and fainting after exercise — may appear up to 15
years before diagnosis.
Funding for this study was provided by the Bogle
Foundation, Campanella family, Wilmerding Endowments,
National Institutes of Health, Donald W. Reynolds
Foundation and W.W. Smith Charitable Trust.
In addition to Judge and Awad, other researchers
involved in this study, conducted solely at Hopkins, were
Darshan Dalal, Eunpi Cho, Nuria Amat Alarcon, Cynthia
James, Crystal Tichnell, April Tucker, Stuart Russell,
David Bluemke, Harry Dietz and Hugh Calkins. Calkins
receives research support from device manufacturers
Guidant, Medtronic and St. Jude. The terms of these
arrangements are being managed by The Johns Hopkins
University in accordance with its conflict-of-interest