Download Dilated Cardiomyopathy (DCM)

Dilated Cardiomyopathy (DCM)
DCMNext is a multi-gene panel for patients with inherited DCM. Mutations
in TTN have been found in about 20% of those with non-ischemic or
idiopathic DCM, with mutations in 31 additional genes accounting for at
least another 10-20%.1 Often, DCM can be asymptomatic and sudden death
is the first symptom. Clinical features can be mild or uncertain; genetic
testing may be the most effective way of identifying at-risk individuals or
confirming a diagnosis. 2
test summary
DCMNext is a next generation sequencing (NGS) and deletion/duplication panel of 32
genes associated with inherited DCM (exceptions may be specified). These genes are
included in the comprehensive cardiomyopathy (CMNext) and cardiovascular genetics
(CardioNext) panels.
disease information
DCM occurs in at least 1 in 2,700 individuals worldwide. DCM is characterized by
left ventricular enlargement, with normal wall thickness and systolic dysfunction.1
Approximately half of DCM is caused by ischemic heart disease, which is typically not
genetic. Mutations have been found in up to 35% of patients with non-ischemic DCM.1
Non-ischemic DCM is usually inherited in an autosomal dominant manner, but may also
be autosomal recessive or X-linked. Non-ischemic DCM may present at any stage of life,
but onset usually occurs in the fourth to sixth decade.1
Management for DCM typically includes echocardiograms, electrocardiograms, and
assessment of sudden cardiac death risk. Medical treatment to reduce hemodynamic
stress is common. Implantable cardioverter defibrillator (ICD) or pacemaker placement
may be recommended if arrhythmias are not well controlled, if a patient is at high risk of
sudden cardiac death, or if a particular gene is implicated by genetic testing results (e.g.
LMNA). 3 DCM may present in childhood; treatment can be considered in children and
adults with a high risk for DCM. Heart transplantation may be necessary for patients
that develop end-stage heart failure. 2
heart rhythm society and european heart rhythm association 2011
expert consensus statement2
DCM genetic testing is a Class I recommendation for all patients with DCM and significant
cardiac conduction disease and/or a family history of premature sudden death
•
Once a pathogenic gene mutation is identified in a family, mutation-specific testing of
family members is a Class I recommendation
•
mutation detection rate
DCMNext will find a mutation in 30-40% of patients with non-ischemic DCM, which
represents all known genetic causes (clinical sensitivity). DCMNext will find >96% of
described mutations in the above genes (analytic sensitivity).
benefits of genetic testing
Clarify diagnosis and risk for sudden cardiac arrest
•
Target medical management and prevention of cardiac arrest and other complications
•
Adjust management in those with DCM due to conditions like Duchenne muscular
dystrophy and Danon disease
•
Offer family members genetic testing (for a familial mutation) and implement medical
surveillance to only those that need it
•
Reduce healthcare costs, resources, and anxiety for families
•
OPTIMIZED TEST DESIGN
Ambry’s tests are created to maximize
yield, minimize turnaround time, and
control costs through step-wise testing
when appropriate.
INSURANCE
Ambry is contracted with the majority
of health plans and Medicare. All outof-network patients are treated as innetwork to minimize out-of-pocket costs.
Medicaid coverage varies by state and
preverification is recommended.
PATIENT PROTECTION PLAN
If your patient’s out-of-pocket financial
responsibility is potentially greater than
$100, Ambry will contact him/her for
verbal approval prior to initiating the
test. We remain committed to working
with you and your patients to make the
genetic testing process as simple and cost
effective as possible.
CLINICAL SUPPORT
Board-certified physicians and genetic
counselors are available to assist with test
selection and result interpretation.
CUSTOMER SERVICE
Responsive, knowledgeable
representatives are always ready
to answer your questions. We also
offer easy-to-read result reports and
complimentary sample submission kits to
make the testing process smoother.
ABOUT AMBRY GENETICS
Since 2001, we have performed hundreds
of thousands of genetic tests, and
identified more than 45,000 mutations in
greater than 500 different genes.
Dilated Cardiomyopathy (DCM)
test description
specimen requirements
DCMNext includes 32 genes associated with DCM. These
genes are also included in the comprehensive cardiomyopathy
(CMNext) and cardiovascular genetics panel (CardioNext).
Genomic deoxyribonucleic acid (gDNA) is isolated from the
patient’s specimen using a standardized kit and quantified.
Sequence enrichment of the targeted coding exons and adjacent
intronic nucleotides is carried out by a bait-capture methodology
using long biotinylated oligonucleotide probes followed by
polymerase chain reaction (PCR) and NGS. Additional Sanger
sequencing is performed for any regions missing or with
insufficient read depth coverage for reliable heterozygous
variant detection. Suspect variant calls other than “likely benign”
or “benign” are verified by Sanger sequencing in sense and
antisense directions. This assay targets all coding domains
and well into the flanking 5’ and 3’ ends of all the introns and
untranslated regions. Gross deletion/duplication analysis for
available genes is performed utilizing a targeted chromosomal
microarray (for all genes except TBX1 and TXNRD2).
Blood: Collect 6-10cc (adult) or at least 5cc (children) in purple top
EDTA tube (preferred) or yellow top citric acetate tube. Storage:
2-8°C and do not freeze. Shipment: Room temperature for twoday delivery.
Blood Spot: Blood spots are not accepted.
Saliva: Fill 2 tubes with saliva up to black line (1cc of saliva)
in Oragene Self Collection container. Close tube; 1cc of buffer
will mix with saliva for a total volume of 2cc. Store at room
temperature in sterile bag. Shipment: Room temperature for twoday delivery.
DNA: 20 µg of DNA in TE (10mM Tris-Cl pH 8.0, 1mM EDTA);
preferred 200 µl at ~100 ng/µl. Please provide DNA OD 260280 ratio (preferred 1.7-1.9) and send agarose picture with high
mw genomic DNA, if available. Store at -20°C. Ship frozen on dry
ice (preferred) or ice. It is recommended if DNA has undergone
multiple freeze/thaw cycles that it not be submitted.
Cultured Cells: We accept cultured cells from fibroblasts. Prefer two
T25 cell flasks (one flask is acceptable) or suitable alternative at
80% confluence. Store at 2-8°C in tissue culture incubator up to
72 hours. Do not freeze. Please call ahead when sending prenatal
samples.
TEST CODES ASSOCIATED TESTS
TURNAROUND TIMES
8884
DCMNext (ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CSRP3, DES, DMD, EYA4, FKTN, LAMA4, LAMP2,
LDB3/ZASP, LMNA, MYBPC3, MYH6, MYH7, MYPN, NEXN, PLN, RAF1, RBM20, SCN5A, TCAP, TMPO,
TNNC1, TNNI3, TNNT2, TPM1, TTN, TXNRD2, VCL)
6-8 weeks
8886
CMNext (ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD,
EYA4, FKTN, FXN, GATAD1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3/ZASP, LMNA, MYBPC3, MYH6,
MYH7, MYL2, MYL3, MYOZ2, MYPN, NEXN, PKP2, PLN, PTPN11, RAF1, RBM20, RYR2, SCN5A, TCAP,
TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTR, TXNRD2, VCL)
6-8 weeks
8887
CMNext plus TTN
8-10 weeks
8910
CardioNext (ABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2,
CALM1, CASQ2, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, EYA4, FKTN, FXN, GATA4,
GATAD1, GLA, GPD1L, HCN4, JAG1, JPH2, JUP, KCND3, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5,
KCNJ8, KCNQ1, LAMA4, LAMP2, LDB3/ZASP, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYOZ2,
MYPN, NEXN, NKX2.5, PKP2, PLN, PTPN11, RAF1, RBM20, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A,
SNTA1, TAZ, TBX1, TBX5, TBX20, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN,
TRPM4, TTR, TXNRD2, VCL)
8-10 weeks
8911
CardioNext plus TTN
10-12 weeks
references
1. Hershberger RE, Morales A. Dilated Cardiomyopathy Overview. 2007 Jul 27 [Updated 2013 May 9]. In: Pagon RA, Adam MP, Ardinger HH, et al.,
editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/
NBK1309/
2. Adapted from Ackerman MJ, et al. HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies. Heart Rhythm. 2011 Aug;8(8):1308-39.
3. Brodt C, et al. Temporal relationship of conduction system disease and ventricular dysfunction in LMNA cardiomyopathy. J Card Fail. 2013.
Apr;19(4):233-9.
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