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Genetic Testing for HCM: What Do We Learn?
And do genotype-negative patients have HCM?
T
here is the concept of big data, in which
important knowledge can be gleaned from
an analysis of the clinical experience of
millions of patients. Then there is the explosion of
molecular data in which one report by Ashley et al.
presented the results of a single patient based on an
analysis of 2.6 million single nucleotide polymorphisms.1 This suggests large—even humongous—
untapped opportunities to use data to improve
health outcomes
A few years ago, the National Research Council
proposed a new data network to integrate emerging
research on the molecular makeup of diseases with
clinical data on individual patients.2 Success here
could drive the development of a more accurate classification of disease and ultimately enhance diagnosis and treatment.
“Currently, a disconnect exists between the
wealth of scientific advances in research and the incorporation of this information into the clinic,” said
Susan Desmond-Hellmann, MD, MPH, co-chair of
the committee that authored the report and Chancellor of the University of California, San Francisco,
CA. “Often it can take years for biomedical research
information to trickle to doctors and patients, and
in the meantime wasteful health care expenditures
are carried out for treatments that are only effective
in specific subgroups.”
In his 2015 State of the Union Address, U.S.
President Barack Obama announced the Precision
Medicine Initiative, a research effort to revolutionize
how we improve health and treat disease. Launched
with a $215 million investment, the concept of
“precision medicine” (an evolution to what has been
called personalized medicine) was used in that
Nati onal Research Council monograph mentioned
above,1 in which the authors explain that their use
of “precision” was intended to avoid the implication
that medications would be synthesized personally
for single patients. Rather, they hoped to convey
a broader concept that would include precisely
tailoring therapies to subcategories of disease, often
defined by genomics.
BIOBANKING AND DATA SHARING
Precision medicine will require a large cohort of
individuals willing to share their electronic medical
and genomic data. Recently, Euan A. Ashley, MD,
of the Departments of Medicine and Genetics in
California’s Stanford University, noted that the first
generation of genomic data will mostly come from
genotyping chips containing 1 million to 2 million
previously identified genetic variants or enhanced
exome sequencing, which targets the sequence of
26 CardioSource WorldNews
the approximately 20,000 genes.3
Some countries, such as the United Kingdom
and Denmark, already have large-scale biobanks. In
the United States, Dr. Ashley noted that the Million
Veteran Program reports recruitment currently at
more than 300,000 individuals, with thousands
having been sequenced and hundreds of thousands
having been genotyped. Other U.S.-based cohorts
include the eMERGE consortium (funded by the
National Human Genome Research Institute),
which combines electronic medical record data and
genomic data from almost 200,000 individuals.
Although challenges remain, results published
by Dr. Ashley and colleagues suggest that wholegenome sequencing can yield useful and clinically
relevant information for individual patients.1
HYPERTROPHIC CARDIOMYOPATHY
Hypertrophic cardiomyopathy is an inherited disease of the heart muscle and among the most common Mendelian cardiac diseases, occurring in one
in 500 people. Advances in genetics have facilitated
identification of a subpopulation of patients with
pathogenic variants in cardiac sarcomere genes. As
Dr. Ashley noted recently in the Journal of the American College of Cardiology (along with Matthew T.
Wheeler, MD, PhD) coding regions of numerous
cardiac sarcomere genes are routinely sequenced
in clinics today.4 Excluding those patients with
discrete upper septal thickening, clearly pathogenic
variants are identified in 30% to 50% of patients,
thus marking a subset of “sarcomeric” HCM.
Genetic testing can tell a lot, according to Dr.
Ashley, ranging from important information regarding optimal management strategies to risk and
response to drugs. As he and colleagues reported in
JACC,5 for example, there are distinctive clinical and
biophysical features that characterize HCM associated with thin-filament mutations that differ from
the more common thick-filament disease. Thin-filament HCM is associated with less prominent and
atypically distributed LV hypertrophy, increased LV
fibrosis, higher likelihood of adverse LV remodeling leading to functional deterioration, and more
frequent occurrence of triphasic LV filling, reflecting profound diastolic dysfunction.
So do genotype negative patients have HCM?
As Dr. Ashley explained, some patients may suffer
from “HCM of the elderly.” Such patients were once
referred to as having discrete upper septal hypertrophy. Today, a more accurate way of expressing that
is discrete upper septal thickening where there is a
sigmoid septum but LV mass and papillary muscles
are often normal; gradients can be high and ventri-
To listen to the
interview with Euan
A. Ashley, MD, visit
the CSWN YouTube
channel or scan
the QR below.
Interview conducted
by Christopher M.
Kramer, MD.
culo-vascular stiffness is common, but family history is rare.
What is this? A non-sarcomeric
form of HCM? It’s sarcomeric,
but the protein is unknown?
Is it just hypertension or some
complex genetic disease? Is it
multifactorial disease or just
a variation of normal? There
is no simple answer, said Dr.
Ashley. It is certainly associated
with age but, when seen in isolation, it does not
appear to have any effect on mortality. “There is no
perfect answer,” he said, “but we all deal with this
uncertainty.”
Another group of genotype-negative patients are
represented by a 17-year-old male who presented
in his early teens with a significant family history,
and family screening revealed even more cases than
previously known. The patient had a moderate
gradient, high LV mass, a lot of delayed-gadolinium
enhancement, and ventricular tachycardia.
At AHA.14, Dr. Ashley reported unpublished
data from the Stanford Cardiome Study: they have
found 64 HCM patients who are genotype negative.
“These are the patients we scratch our heads over
the most,” he said. “We see patients who appear to
have classic hypertrophic cardiomyopathy: reverse
curvature and asymmetry, but negative sarcomere
sequencing—as we currently do sarcomere sequencing today.”
It may be a coding variant in a gene of the
cardiac sarcomere that is not on the sequencing
panel. Maybe it’s a regulatory variant in a sarcomere
gene or a variant in a non-sarcomere gene, such as
a signaling gene. We know a number of signaling
pathways that cause hypertrophy. Could some of
them cause an asymmetric hypertrophy? Or maybe
there is epigenetic modification of a sarcomere gene.
At least we are probably confused at a higher level
than was possible just a few years ago.
He added, “We offer genetic testing to all our
HCM patients at Stanford and spend a significant
amount of time on family history and thinking
about the whole family as our patient.” There is no
clear answer, he admits, to the question of whether
genotype-negative patients have HCM. “I am not
sure I have answered that question for you.” Some
do, he said, and some don’t; there is probably a useful debate to be had around the issue of semantics.
Overall, Dr. Ashley said that development of
methods integrating genetic and clinical data will
assist clinical decision-making and represents a
large step towards individualized medicine. The
October 2015