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Test Information Sheet
Hypertrophic Cardiomyopathy Panel
Up to 60 genes
The Hypertrophic Cardiomyopathy Panel is a comprehensive next-generation sequencing (NGS) panel that
can be used to confirm a clinical diagnosis of hypertrophic cardiomyopathy or identify at-risk individuals.
Hypertrophic cardiomyopathy is characterized by thickening of the heart muscle, which may cause obstruction
of blood flow out of the left ventricle or decreased efficiency in pumping blood. Symptoms of the condition
may include chest pain, shortness of breath, lightheadedness, and fainting, although many individuals will
not have any symptoms of the condition at all. Hypertrophic cardiomyopathy can lead to abnormal heart
rhythms or heart failure in some individuals. The condition increases a person’s risk for sudden cardiac
death, even in the absence of other symptoms.
PREVALENCE
The prevalence of hypertrophic cardiomyopathy is approximately 1 in 500, with some estimates as high as 1 in
200 (Semsarian et al, 2015).
INCLUDED DISORDERS
This panel includes genes related to primary hypertrophic
cardiomyopathy as well as genes associated with
disorders that include hypertrophic cardiomyopathy as a
feature. These disorders include:
a causative mutation can be identified (with mutations in
MYH7 and MYBPC3 accounting for 80% of cases).
METHODOLOGY AND ANALYTICAL SENSITIVITY
Next-generation sequencing technology is used to
test clinically relevant portions of each gene, including
coding exons, adjacent intron/exon boundaries, and
selected introns/noncoding variants. Pathogenic and
likely pathogenic variants are confirmed by orthogonal
methods. Copy number variants, including intragenic
deletions and duplications are detected to a resolution of
single exon. To request analysis of a specific single exon
copy number variant, please contact our Client Services
team prior to ordering. Analytical sensitivity of the assay
is >99%.
•
Danon disease
•
Fabry disease
•
Myofibrillar myopathy
•
Timothy syndrome
•
Transthyretin (TTR) amyloidosis
•
Wolff-Parkinson-White syndrome
INHERITANCE AND PENETRANCE
•
Other disorders
Hypertrophic cardiomyopathy is typically inherited in an
autosomal dominant fashion, meaning that an affected
individual has a 50% chance of passing on the condition,
although some forms are inherited in recessive, and
X-linked manner. Hypertrophic cardiomyopathy typically
exhibits reduced and age-related penetrance, meaning
that not all individuals with a pathogenic mutation will
develop disease, and that the risk for symptoms of the
disease increases with age.
CLINICAL SENSITIVITY
A genetic mutation causing hypertrophic cardiomyopathy
can be identified in approximately 60% of probands
with familial disease, and in 20-30% of isolated cases
(Gersh et al, 2011). The Hypertrophic Cardiomyopathy
panel includes the genes most commonly involved
in hypertrophic cardiomyopathy. Mutations in genes
included in the HCM core panel are expected to account
for >90% of cases of hypertrophic cardiomyopathy where
© Phosphorus 2017
www. phosphorus.com | 1-855-746-7423 | [email protected]
032017 HCMTIS 1.0
INDICATIONS FOR TESTING:
•
Confirmation of clinical diagnosis
•
Unexplained cardiac arrrest
•
Risk assessment for asympotamic family members of proband with molecular diagnosis of hypertrophic
cardiomyopathy.
INCLUDED GENES (27):
ACTC1
AGL
BAG3
BAG3
CACNA1C
CAV3
CSRP3
DES
FHL1
FLNC
GAA
GLA
LAMP2
LDB3
MYBPC3
MYH7
MYL2
MYL3
PLN
PRKAG2
TCAP
TNNC1
TNNI3
TNNT2
TPM1
TTR
VCL
ADDITIONS TO COMPREHENSIVE PANEL
Emerging Evidence Genes (11)
Emerging evidence genes can also be added on to the comprehensive panel. These genes do not have a clear
association with Long QT syndrome, but emerging evidence suggests that they may play a role in disease pathogenesis:
ANKRD1
CAL3
NEXN
PDLIM3
GATA4
JPH2
MYH6
MYLK2
MYOM1
MYOZ2
MYPN
RASopathies Genes (18)
Genes associated with the RASopathy spectrum of disorders, which frequently include hypertrophic cardiomyopathy
as a symptom, may be added onto the Hypertrophic Cardiomyopathy panel.
Mutations in genes related to the Ras/MapK cell signaling pathway cause a group of related disorders known as the
RASopathies. These disorders include Noonan syndrome, Cardiofaciocutaneous (CFC) syndrome, Costello syndrome,
neurofibromatosis (NF), LEOPARD syndrome, and Legius syndrome, among others. The Ras/MapK pathway is involved
in cell growth, differentiation, proliferation, and death. The Ras/MAPK spectrum of disorders shows both locus and
allelic heterogeneity, meaning that mutations in different genes can cause the same phenotype, and different mutations
in the same gene can cause different phenotypes, respectively. Although the specific phenotype varies by disease,
many, but not all, of these disorders include hypertrophic cardiomyopathy as a feature.
A2ML1
MAP2K2
RIT1
BRAF
NF1
RRAS
CBL
NRAS
SHOC2
HRAS
PTPN11
SOS1
SOS2
KRAS
RAF1
MAP2K1
RASA1
SPRED1
Syndromic Pediatric Genes (4):
Genes associated with pediatric syndromes inherited in an autosomal recessive manner that present with hypertrophic
cardiomyopathy as feature can also be added to the Hypertrophic Cardiomyopathy Panel.
ACADVL
CPT2
ELAC2
MTO1
REFERENCES
1. Cirino AL, Ho C. Hypertrophic Cardiomyopathy Overview. 2008 Aug 5 [Updated 2014 Jan 16]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors.
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
2. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and
cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm
Association (EHRA). Heart Rhythm. 2011;8(8):1308-39.
3. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. J
Card Fail. 2009;15(2):83-97.
4. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive
summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation.
2011;124(24):2761-96.
5. Morita H, Rehm HL, Menesses A, et al. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008;358(18):1899-908.
© Phosphorus 2017
www. phosphorus.com | 1-855-746-7423 | [email protected]
032017 HCMTIS 1.0