Methodology:
A combination of oligonucleotide
hybridization-based DNA sequencing using the
Affymetrix GeneChip® platform and dideoxy-based
DNA sequencing of the coding regions and splice
sites of all genes.
Background:
Hypertrophic cardiomyopathy (HCM) is a
primary disorder of the myocardium that is
characterized by unexplained left ventricular
hypertrophy (LVH) in a non-dilated ventricle.
Distinctive findings of myocardial hypertrophy
with myocyte disarray are the histopathologic
hallmarks of this disorder. The clinical
spectrum of HCM is diverse, ranging from
asymptomatic individuals to those with
disabling symptoms of heart failure, exercise
intolerance, and chest pain. HCM is also
associated with an increased risk of sudden
cardiac death.
Genetic studies have defined HCM as a
disease of the sarcomere - caused by
mutations in any of a dozen genes that
encode different elements of the contractile
apparatus in cardiac myocytes. To date, over
700 individual mutations have been identified.
With a prevalence estimated to be ~1/500 in
the general population, HCM is the most
common monogenic cardiac disorder and is
inherited in an autosomal dominant mode. In
addition, defects in genes involved in storage
diseases, such as LAMP2 , PRKAG2 and
GLA , typically cause systemic disease but
may also result in predominant cardiac
manifestations, which can mimic hypertrophic
cardiomyopathy (HCM).
Echocardiographic evidence of unexplained
left ventricular hypertrophy typically forms the
basis for establishing the clinical diagnosis of
HCM, however this finding fails to identify all
affected individuals. Although the gene mutation responsible for causing HCM is inherited at the time
of conception, it may take decades before there is clinically evident expression of LVH. Therefore,
making the clinical diagnosis of HCM early in life may be a particular challenge.
In addition to confirming the diagnosis of HCM in patients with clinically evident disease, genetic
testing allows for early identification and diagnosis of individuals at greatest risk for developing HCM,
prior to the expression of typical clinical manifestations (e.g. LVH). If a mutation is identified in such a
preclinical individual, regular and serial outpatient follow up is indicated. Referral to a cardiologist
with specific expertise in the management of HCM is highly recommended for patients with
established disease as well as family members who are found to have a positive genetic test. Long
term follow-up is necessary to survey for the development of clinical manifestations as well as to
optimize treatment. If clinically unaffected members of a family with an identified causal mutation for
HCM are found not to carry that mutation (genotype negative), they can be definitively diagnosed as
unaffected with HCM and reassured that neither they nor their children will be at higher risk compared
to the general population to develop this disorder. Serial follow up is no longer needed.
Based on previous testing of the top 8 HCM genes (MYBPC3, MYH7 , TNNI3 , TNNT2 , TPM1 , ACTC ,
MYL2 , MYL3 ) in 750 cases in the Laboratory for Molecular Medicine, the likelihood of identifying an
HCM mutation in a patient with features of HCM is approximately 51% (40% for isolated cases and
66% for cases with a positive family history of either HCM or sudden cardiac death). Our new test, the
HCM CardioChip, sequences 11 genes (MYBPC3, MYH7 , TNNI3 , TNNT2 , TPM1 , ACTC , MYL2 ,
MYL3 , LAMP2 , PRKAG2 , GLA ) known to cause HCM using a novel method of DNA sequencing.
Methodology: The HCM CardioChip Test is performed by a combination of oligonucleotide
hybridization-based DNA sequencing of the coding regions and splice sites of the MYH7 , MYBPC3,
TNNT2 , TNNI3 , TPM1 , ACTC , MYL2 , MYL3 , LAMP2 , PRKAG2 , and GLA genes using a custom
design on the Affymetrix GeneChip platform as well as dideoxy-based DNA sequencing of the coding
regions and splice sites of MYBPC3. This test does not detect all mutations in non-coding regions
that could affect gene expression or deletions encompassing a large portion of the gene.
Analytical Sensitivity: The HCM CardioChip Test detects over 98% of HCM-causing mutations in
the 11 genes tested.
Clinical Sensitivity: Based on results from the first 750 cases tested in the Laboratory for Molecular
Medicine, the likelihood of identifying an HCM mutation in one of the 8 sarcomere genes ( MYH7 ,
MYBPC3, TNNT2 , TNNI3 , TPM1 , ACTC , MYL2 , MYL3 ), in a patient with features of HCM, is
approximately 51% (40% for isolated cases and 66% for cases with a positive family history of either
HCM or sudden cardiac death).
