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Arrhythmia Genetic Testing A Comprehensive Guide A cardiac arrhythmia is defined as an irregular heart rhythm caused by abnormal electrical activity. The abnormal electrical activity can cause the heart to beat too rapidly, too slowly, or erratically, and may interfere with the heart’s ability to efficiently pump blood throughout the body. Many arrhythmias are harmless and resolve quickly; however, a prolonged arrhythmia event can be serious and even life-threatening. The risk for arrhythmias can be influenced by a number of common factors including heart disease, high blood pressure, stress, caffeine, smoking, alcohol use, and certain medications. However, in some instances, individuals are born with a genetic predisposition to develop severe cardiac arrhythmias over their lifetime. In many cases, these genetic predispositions to arrhythmias are caused by a harmful change (pathogenic variant) in one of the genes encoding the ion channel proteins that regulate the electrical activity of the heart. Pathogenic variants in these ion channel genes, as well as pathogenic variants in genes that encode channel-interacting proteins, can cause inherited cardiac arrhythmias. Collectively, these disorders are referred to as channelopathies. Genetic testing can determine if a person carries a pathogenic variant in a gene that has been associated with an inherited arrhythmia syndrome. Testing may also provide valuable information about medical management to patients and their family members. Clinical Presentation/Course Arrhythmias can affect individuals of all ages and ethnicities. They may present at differing ages and with variable symptoms, even among members of the same family. The most serious complication of an arrhythmia is sudden death. However, more common signs and symptoms of arrhythmias may include: • Palpitations • A slow or irregular heart rate • Dizziness • Near-syncope or syncope (fainting) • Chest pain GUIDE FOR INHERITED ARRHYTHMIA 1 CLINICAL INFORMATION Inherited Arrhythmias CLINICAL INFORMATION Numerous inherited arrhythmia conditions have been characterized. Although all of the conditions affect the electrical activity of the heart resulting in an abnormal heart rhythm, each condition is also characterized by unique features, some of which are summarized in Table 1. Phenotype Description ARVC is characterized by the replacement of normal heart cells with Arrhythmogenic Right Ventricular Cardiomyopathy fat or fibrotic tissue, predominantly in the right ventricle. The left ventricle may also be affected over time.1,2 (ARVC) Atrial Fibrillation (AF) (Familial) Characteristics suggestive of familial atrial fibrillation include lack of obvious cause or risk factors (idiopathic), young age and family history of multiple family members with AF.3,4 Brugada Syndrome (BrS) Brugada syndrome is characterized by one of several ECG patterns that include ST-segment elevation in the precordial leads, especially the type I pattern with a “coved morphology”. This diagnosis may be suspected due to a personal or family history of unexplained syncope or a unexplained sudden cardiac arrest/death in the absence of structural heart disease.5 Progressive Cardiac Conduction Disease (CCD) Cardiac conduction disorders (CCDs) are typically associated with a delay in electrical impulse conduction at the atrial, nodal and ventricular levels. In an electrocardiogram (ECG), CCDs are characterized by a prolonged P-wave duration as well as PQ interval and QRS widening with axis deviation in the absence of structural heart disease. Not all ECG changes may be present initially, but they can progressively develop associated with age-dependent penetrance.6,7 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) CPVT is characterized by polymorphic ventricular tachycardia in the presence of adrenergic stimulation, particularly in individuals less than 20 years of age. Diagnosis is supported by absence of structural heart disease and induction of bidirectional VT or polymorphic VT by exercise test or by infusion of adrenergic agonist.8 Long QT Syndrome (LQTS) LQTS is characterized by a prolonged QTc interval on ECG or Holter monitor in the absence of an acquired cause of prolonged QT. A prolonged QTc interval is defined as of >450 msec in adult males and >470 msec in adult females, although it is important to note that up to 25% of individuals with a confirmed diagnosis of LQTS have a normal QTc interval. A personal and/or family history of syncope, cardiac arrest, or sudden death in a child or young adult can also lead to suspicion of LQTS.9-13 Short QT Syndrome (SQTS) The characteristic sign for SQTS is the presence of a very short QT interval on ECG. Although a diagnostic value for a short QTc interval has not yet been clearly defined, previous patients have demonstrated mean QTc intervals of approximately 350 ms in males and 365 ms in females.14-16 Table 1: Description of inherited arrhythmia conditions. 2 Diagnosis The diagnosis of an inherited arrhythmia may be considered in an individual and/or family for a number of different reasons, including a combination of personal health history, family health history, and cardiac testing. Other known causes of arrhythmia, including systemic disease, structural cardiac conditions, medications and electrolyte disturbances, should be ruled out before considering genetic testing for an inherited arrhythmia syndrome. Table 2 discusses important evaluations that should be investigated by a physician when considering the diagnosis of an inherited disorder. Things to Consider History, Presence of, or Abnormal Results Family History Information Syncope, seizures, young or unexplained sudden death, drownings, and unexplained single car accidents Physical Examination Rales, edema, heart murmur, or fast or irregular pulse Non-Invasive Testing Chest x-ray, exercise stress test, ECG, Holter or event monitor, signal-averaged ECG (SAECG), tilt table test or echocardiogram Invasive Testing Cardiac catheterization, coronary angiography, electrophysiology study (EPS) or implanted cardiac loop recorder Table 2: Medical history information to consider before undergoing genetic testing for inherited arrhythmia conditions. Information gathered from the evaluations listed in Table 2 can provide valuable insight to determine when genetic testing for an inherited arrhythmia may be appropriate. GUIDE FOR INHERITED ARRHYTHMIA 3 Factors Influencing Clinical Presentation Many of the genes associated with inherited arrhythmias have been shown to have both reduced penetrance and variable expressivity. In other words, patients found to have pathogenic or likely pathogenic variants may or may not experience any cardiac complications over their lifetime (reduced penetrance), or may exhibit different clinical presentations (variable expressivity). This information can help explain why different patients, even members of the same family that carry the identical genetic variant, may have vastly different clinical symptoms and presentations over their lifetimes. Factors to Consider when Ordering Genetic Testing There are several specific recognizable arrhythmia phenotypes and clinical presentations, but there is overlap between the conditions. Nearly all forms of inherited arrhythmia have been associated with more than one gene (genetic heterogeneity), while certain genes have also been associated with more than one specific phenotype (phenotypic heterogeneity). This genetic and phenotypic crossover among inherited arrhythmia conditions can make genetic testing challenging in some individuals and families. For this reason, in certain circumstances a more comprehensive panel could be considered. Characteristic ECG Findings in Select Arrhythmia Conditions Normal LQTS BrS CPVT 4 Arrhythmia CACNA2D1 HCN4 KCNE1L^ CACNB2 Short QT Syndrome (SQTS) NKX2-5 RANGRF ABCC9 GPD1L KCND3 CACNA1C Brugada Syndrome (BrS) KCNE3 KCNJ8 SCN10A SCN1B^ SCN2B SCN3B TRPM4 KCNH2 KCNQ1 Long QT Syndrome (LQTS) AKAP9 ANK2 CAV3 KCNE1 KCNJ2 PKP2 SCN5A KCNE2 KCNJ5 SCN4B SNTA1 PLN TGFB3 TMEM43 TTN CALM1* CALM2 CALM3 TRDN Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) DSP JUP LMNA DES DSC2 DSG2 CASQ2 RYR2 Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) * Del/Dup analysis not offered ^ Gene level resolution; may not detect exon level events GUIDE FOR INHERITED ARRHYTHMIA 5 6 Identification of Patients at Risk for Inherited Arrhythmias Patients or families with one or more of the following may benefit from genetic testing:17-19 • Arrhythmias or “Irregular heartbeat” • Implantable cardioverter defibrillator (ICD) or pacemaker placement at <50 years of age • Unexplained cardiac arrest(s) or sudden death • Sudden infant death syndrome (SIDS) TEST INFORMATION • Unexplained syncope and/or syncope with exercise or emotional distress • Unexplained seizures or seizures with a normal neurological evaluation • Unexplained accidents such as drowning and single car accidents Heart Rhythm Society (HRS) and European Heart Rhythm Association (EHRA) Consensus Guidelines on Genetic Testing for Channelopathies19 Disorder Individuals with a Clinical Diagnosis Asymptomatic Relatives (Familial Mutation Testing) LQTS Class I Class I CPVT Class I Class I BrS Class IIa Class I SQTS Class IIb Class I ARVC Class IIa (For patients meeting the ARVC task force diagnostice criteria) Class I Recommendation Classes Class I: Genetic testing is recommended. Test result impacts diagnosis and/or management recommendations. Class IIa: Genetic testing can be useful for patients with a clinical diagnosis. Class IIb:Genetic testing may be considered as part of the diagnostic evaluation. Class III: Genetic testing is not recommended. GUIDE FOR INHERITED ARRHYTHMIA 7 Arrhythmia Testing Options Test Genes Offerings Arrhythmia Panel ABCC9, AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2, CALM1*, CALM2, CALM3, CASQ2, CAV3, DES, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCND3, KCNE1, KCNE2, KCNE3, KCNE1L^, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, LMNA, NKX2-5, PKP2, PLN, RANGRF, RYR2, SCN10A, SCN1B^, SCN2B, SCN3B, SCN4B, SCN5A, SNTA1, TGFB3, TMEM43, TRDN, TRPM4, TTN TEST INFORMATION Phenotype-Specific Panels Turn Around Time 4 weeks 4 weeks LQTS AKAP9, ANK2, CACNA1C, CALM1*, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1, TRDN BrS ABCC9, CACNA1C, CACNB2, GPD1L, KCND3, KCNE3, KCNJ8, PKP2, SCN10A, SCN1B^, SCN2B, SCN3B, SCN5A, TRPM4 CPVT CALM1*, CALM2, CALM3, CASQ2, KCNJ2, RYR2, TRDN SQTS CACNA1C, CACNB2, KCNH2, KCNJ2, KCNQ1 ARVC DES, DSC2, DSG2, DSP, JUP, LMNA, PKP2, PLN, RYR2, SCN5A, TGFB3, TMEM43, TTN Other Testing Options Combined Panel 4 weeks ABCC9, ACTC 1, ACTN2, AKAP9, ALMS1, ALPK3, ANK2, ANKRD1, BAG3, BRAF, CACNA1C, CACNA2D1, CACNB2, CALM1*, CALM2, CALM3, CASQ2, CAV3, CHRM2, CRYAB, CSRP3, DES, DMD, DOLK, DSC2, DSG2, DSP, DTNA, EMD^, FHL1, FKRP*, FTKN, GATAD1, GLA, GPD1L, HCN4, HRAS*, ILK, JPH2, JUP, KCND3, KCNE1, KCNE2, KCNE3, KCNE1L, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1,KRAS, LAMA4, LAMP2, LDB3, LMNA, MAP2K1, MAP2K2, MIB1, MTND1*, MTND5*, MTND6*, MTTD*, MTTG*, MTTH*, MTTI*, MTTK*, MTTL1*, MTTL2*, MTTM*, MTTQ*, MTTS1*, MTTS2*, MURC, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NKX2.5*, NRAS, PDLIM3, PKP2, PLN, PRDM16, PRKAG2, PTPN11, RAF1, RANGRF, RBM20, RIT1, RYR2, SCN10A, SCN1B^, SCN2B, SCN3B, SCN4B, SCN5A, SGCD, SNTA1, SOS1, TTAZ^, TCAP, TGFB3, TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, TTR, TXNRD2, VCL * Del/Dup analysis not offered ^ Gene level resolution; may not detect exon level events Additional testing options are available, including targeted variant testing for a previously identified variant(s). Appropriate test selection depends on the specific clinical history of a patient, including family and personal health histories as well as familial test results. Testing for most genes includes sequencing and deletion/ duplication analysis via next-generation sequencing and array CGH with exon level resolution, respectively. 8 Sample Submission Genetic testing can be performed on blood, oral rinse, or extracted DNA samples. GeneDx test kits are available to ordering providers, and include sample collection items (such as mouthwash for oral rinse and collection tubes), the necessary sample submission paperwork, and a self-addressed return shipping label. Additionally, all test requisition forms are available for download from the GeneDx website: www.genedx.com/forms Please note that all testing must be performed under the guidance of a health care provider. For more information on the sample submission process, please visit our website: www.genedx.com/supplies or email us at: [email protected] Cardiology Test Requisition Form Patient Information Sample Information First name Last name Gender ❒ Male ❒ Female Date of birth (mm/dd/yy) _______________________ Ancestry ❒ Caucasian ❒ Eastern European ❒ Northern European ❒ Western European ❒ Native American ❒ Middle Eastern ❒ African American ❒ Asian ❒ Pacific Islander ❒ Caribbean ❒ Central/South American ❒ Ashkenazi-Jewish ❒ Hispanic ❒ Other: ______________ Medical record # City State Zip code Work phone Statement of Medical Necessity Patient's primary language if not English This test is medically necessary for the diagnosis or detection of a disease, illness, impairment, symptom, syndrome or disorder. The results will determine my patient's medical management and treatment decisions. The person listed as the Ordering Account Information Acct # Account Name Reporting Preference*. ❒ Care Evolve ❒ Fax ❒ Email that I have provided genetic testing information to the patient and they have consented to genetic testing. *If unmarked, we will use the account's default preferences or fax to new clients. Physician Date sample obtained (mm/dd/yy) Patient has had a bone marrow transplant/transfusion ❒ Yes ❒ No Date of last transfusion __/__/__ (must be at least 2 weeks prior to blood draw for testing) Clinical Diagnosis: _____________________ ICD-10 Codes: ______ Age at Initial Presentation: _______ Mailing address Home phone Specimen ID ❒ Blood in EDTA (5-6 mL in lavender top tube) ❒ DNA (>20 ug): Tissue source ______ concentration ___ (ug/ml) Vol ___(ul) ❒ Oral Rinse (At least 30 mL of Scope oral rinse in a 50 mL centrifuge tube) ❒ Dried Blood Spots (2 cards) - Not accepted for any testing with a del/dup component ❒ Other __________________________(Call lab) NPI # Medical Professional Signature (required) Date Patient Consent (sign here or on the consent document) Genetic Counselor I have read the Informed Consent document and I give permission to GeneDx to perform genetic testing as described. I also give permission for my specimen and Street address 1 Street address 2 City State Phone testing and for publication, if appropriate. My name or other personal identifying information will not be used in or linked to the results of any studies and publications. I also give GeneDx permission to inform me in the future about research opportunities, including treatments for the condition in my family. ❒ Check this box if you wish to opt out of any research studies. ❒ Check this box if you do not wish to be contacted. ❒ Check this box if you are a New York state resident, and give permission for GeneDx to retain any remaining sample longer than 60 days after the completion of testing. Zip code Fax (important) Email Beeper Send Additional Report Copies To: Physician or GC/Acct # Fax#/Email/CE # Physician or GC/Acct # Patient/Guardian Signature Fax#/Email/CE # Date Payment Options Insurance Bill Referral/Prior Authorization # ____________________ Insurance Carrier Policy Name Insurance ID # Group # Secondary Insurance GeneDx Benefit Investigation # Name of Insured Insurance ID# Group # Date of Birth Name of Insured Please attach copy of Referral/authorization Insurance Address Date of Birth City State Zip Relationship to Insured ❒ Child ❒ Spouse ❒ Self ❒ Other _______ Carrier Name Relationship to Insured ❒ Child ❒ Spouse ❒ Self ❒ Other _______ Please include a copy of the front and back of the patient’s insurance card (include secondary when applicable) If you would like to expedite the eligibility requirements for consideration of Financial Assistance, please provide number of Household Members _______ and Annual Adjusted Gross Income ______________. I represent that I am covered by insurance and authorize GeneDx, Inc. to give my designated insurance carrier, health plan, or third party administrator (collectively "Plan") the information on this form and other information I will cooperate fully with GeneDx by providing all necessary documents needed for insurance billing and appeals. I understand that I am responsible for sending GeneDx any and all of the money that I receive directly from my law. I permit a copy of this authorization to be used in place of the original. Patient Signature (required)____________________________________________________________________________________ Date _____________________________ Institutional Bill Patient Bill Amount _______________ I understand that my credit card will be charged the full amount for the testing. Please bill my credit card (all major cards accepted) ❒ Visa ❒ Discover ❒ American Express GeneDx Account # ❒ MasterCard Hospital/Lab Name Name as it appears on card Contact Name Address City Phone © GeneDx 02/16 State Zip Code Account Number Expiration date Signature Date CVC For GeneDx Use Only Fax 207 Perry Parkway, Gaithersburg, MD 20877 • T: (888) 729-1206 (Toll-Free), (301) 519-2100 • F: (201) 421-2010 • www.genedx.com GUIDE FOR INHERITED ARRHYTHMIA 9 Page 1 of 7 10 Genetic Test Results Nearly all test results fall into one of four categories: 1. Positive Result (pathogenic variant(s)) 2. Likely Pathogenic Variant Result 3. Variant of Uncertain Significance (VUS) Result 4. Negative Result (no variants of clinical significance) GeneDx test reports contain detailed information about a specific genetic result and, if available, medical management options. Genetic counseling is recommended prior to genetic testing to understand the benefits and limitations of testing and after genetic testing to discuss the implications of the genetic test results. Genetic counseling services across the country can be found at www.nsgc.org Positive Result A positive result indicates a pathogenic (diseasecausing) genetic variant (change) was identified in a specific disease gene. This finding confirms an underlying genetic cause for the patient’s symptoms and provides a diagnosis of a specific genetic disorder, or indicates an increased risk for developing a genetic disorder. Knowledge of the specific pathogenic variant(s) provides valuable information to the patients, their health care providers and family members because it helps to determine the recurrence risk and to develop an appropriate medical management plan. A medical management plan may include lifestyle modifications, ongoing screening, preventative medications and measures, and/ or surgical/medical device interventions. Furthermore, a positive genetic test result allows targeted testing of at-risk relatives to determine if any of them carry the pathogenic variant(s) as well as to address the recurrence risk of the disorder in future offspring. Cardiolo Nam e: Pati ent Birt h: Dat e of e: en Typ Spe cim No: ers ID Sub mitt By: Ord ered : Requested Test(s) uated: Genes Eval Result: tion: Interpreta gy Gene tics Repo No: Patient Name:eDx Acc essi on d: Gen Obt aine Date of Birth:e Spe cim en d: Dat Rec eive cim en Specimen Type: Dat e Spe ted: (s) Star Submitters ID No: Date Test Ordered By: e of Rep ort: Dat rt Cardiology Genetics Report GeneDx Accession No: Date Specimen Obtained: Pat ien t Na me Da te Date Specimen Received: of Bir : th: Spe cimDate en TypTest(s) Started: Sub mit e: Report: Date of ter s ID Or der No : ed By 3, : Card iology Genet eDx Gene Dx - 207 Perry Parkway GeneDx 207 Perry Parkway 20877 rg, MD Gaithersbu - - 207 Perr y Park way - ics Re Gait hersburg 1 of 6 , MD 2087 - Page 7 genedx.com Tel (301 - www. ) 519421-2010 2100 Fax (201) 519-2100 Tel (301) Gaithersburg, MD 20877 Tel (301) 519-2100 Fax (201) 421-2010 Fax (201 - ) 421- 2010 www.genedx.com www- Page 2 of 6 .genedx. com - Page GUIDE FOR INHERITED ARRHYTHMIA 3 of 6 11 port RESULTS / MANAGEMENT CAVbeen reported in approximately 25-35% of patients with autosomal Q2, KCNH2 Summary: Pathogenic gene have J2, Ge neD Panel variants in the KCNH2 CAS SCN ication 10AKCN CALM3, x Ac p.R512 QTM2, syndrome (LQTS), andH2, are SCN associated 3B, with increased risk of cardiac events triggered by exercise tion/Dupl dominant longCAL ces Da te E1L, KCN Q: M1, g and Dele Spe cim sio n No E3, KCN SCN2B, and, CAL auditory stimulation, especially during sleep (Alders and Mannens, 2012). Although predominantly associated : Da te Sequencin en Ob p.A CACNB2 E1, KCNE2, KCN 10A, SCN1B, ythmia NA2D1, D3, KCN tai ned with LQTS, heterozygous been QT Spe cim 2Glnreported in association with shortDa 2, SCN pathogenic variants in KCNH2 have alsorg51 nsive Arrh en Re C, CAC (R512Q te Tes GRF, RYR Comprehe A vari of pathogenic cei ved : syndrome (SQTS) (MIM: 609620). In addition, asymptomatic carriers KCNH2 variants have been JUP, KCN CACNA1 ) (CG t(s) Sta ant of HCN4, PKP2, PLN, RAN TTN A>C ANK2, : publish unc AA): 2012). Da te of M4, indicating reduced penetrance for KCNH2-related reported, cardiac disease (Alders AKAP9, , GPD1L, erta and Mannens, 2.5, Rep ort rted: ion c.1535 N, TRP was not ed as a path in significa ABCC9, 2, DSG2, DSP LMNA, NKX G>A Classificat : M43, TRD nt in exo Variain Americ observed ogenic vari nce has DES, DSC J8, KCNQ1, TGF B3, TME genicA>G n KCNH2 p.N629S: p.Asn629Ser (N629S) (AAC>AGC): c.1886 exon 7 of the KCNH2 gene (NM_000238.2) bee 11 with sity an ant, KCN Patho n iden of the anc Zygo a sem any sign nor SNTA1, tified KCNJ5, SCN i-conser estry in ous ifica has it bee 10A SCN5A, some the SCN vative the in gene n repo in NHLBI nt freqwith Heterozyg variant in the KCNH2ion SCN4B, propertie The(N62 N629S gene has been reported previously (Satler et10A Variant 9S) pathogenic uencyLQTS (NM amino association rted Glu ificat Exo _00651 as a gene. Ser s. How in app Class et al., 2008; me Seq Christiansen acid et DNA ine2002; rtain protettam al., Goldenberg E subal., 4.2) p.Asn629 al., 1998; Kapplinger et al., 2009; Zhang nt uencing roximatet benign vari The R51 stitu2011; of Unce Moss Coding ein stru is the wild ever, this POSITIV ely 2Q vari ant Varia variant Pro substitu tionindividuals , whi al., 2014; Riuro et sity al., 2014). The N629S unrelated tested Zygo cture/fuin multiple type ject or for6,500 indi to our 6 A>G ce has also been observed ant ch in tion fican c.188 kno may ous several in the viduals Gene Signi wledge has not bee occurs on. samples RecN629S imp rozyg at GeneDx. In addition, in refo approximatelyncti 6,500 from individuals of 100 omm was not observedThe spec Variant LQTS (HERG) 2Q) Hete re, base ies. Fina at a pos act seconda 0 Genomeof Europe . The R51 n endatio 46 This Exome TION KCNH2 of the Gln (R51 and African American backgrounds European in the NHLBI Sequencing Project, indicating itlly, is not aition that ry prot d on result n: sis s Pro an and Afr 2Q vari RPRETA Coding DNA in silic p.Arg512 cannot the curr ein ject ant ence analyFunctional urrent1.studies entl protein-trafficking causing o ana sequ SEE INTE common benign variant in these populations. a lysiis not conserv structure . The R51 ican be inte affects It is recoreport N629S by conc G>A ified by as thes rpreted y available 2Q vari foundprotein c.1535 folloresulting e resi dominant-negative effect onzed thewas normal complex, loss of normal iondiag channel function (Anderson ets predicts thised across spec Gene informa a were ident for yDx. w-up mminend dues ant is thmi Arra ed analy s tion nosis variant for arrh at the ies that this codon (N629D, diff Exon , it isN629K, al.,arrhy 2006).the Located pore ofiathe KCNH2 gene, multiple N629I, 45 genein the or used SCN10A ythm , variants ythm same likely and where er in iated with unclear individu 2. Bas ia. the Arrh in nearby residues any of as for fam H2 gene does to be associnvolving whether al and N629T), well as variants G628S, S631A) have alsoilybeen ed on G628V, V630A, V630L, ded on not alte rtain the KCN(G628A, known n inclu ava in any mem nts unce this this not ic catio of r the ilab is first-deg varia gen ber scre variant dupli reported in HGMD inisassociation (Stenson gene for2014). pathogen with variant mem etleal., aLQTS this fam etic test ree rela is pathogenic No deletion or The CALM1 ening bers nt that gous for l. ). at this pathogenic tives No other presenc . Testing ily, and result, targ receive ense variais also heterozy time. this pane (ExonArrayDx or rare eted is reco variant, continu genes on theuspathcan dist In summary, asevario aofpathogenic variant. benign. ished miss mmend genetic idual N629S in the KCNH2 gene is interpreted ingu array CGH ed clin for a publ This indiv s that cause not the full ogenic vari ish family ed for all testing for targeted ical eva rozygous arrhythmia. of gene 3.ate the the N62 mem of this ant.indicate Arrhyth sis hete luat is of l bers Gen SCN10A Summary: The SCN10A gene encodes a sodium ion channel and in vitro studies in mice this gene is expressed in analy ion and 9S vari any affe idua mia pan etic form at incr individu that medi Ifregul atory uplicationmyocardium, ant al's eased . cted muscle and inthethe This indivt with a genetic ion/d R51 sensory neurons, ventricular cardiac conduction (Okusetesti etng al.,of2002; individu systemel. risk of firstet 2Q -degree in the KC other Sotoodehnia 10A gene and delet ins of the heart as their associated withic right NH ence dev consisten ce in the SCN diseasevariant rela prote sequ al., 2010). Heterozygous pathogenic the SCN10A gene with do reported in associationfam ily cardiac well variants in in havealsbeen ogen mem eloping fam tives and 2 gene is cells, as ders. Arrhythm thatin this famthe SCN10Anot harbor l includes for ion channel bers now lex interval, significan ilial arrh other ia Pane ed ily. syndrome, cardiacincluding conduction defects prolongation ofinthe QRS the atrial comp 4. Gen disor gene and at-risk cterizBrugada N629Sfibrillation; reduced only requ ourcaes: Arrhythm these genes code in and out of arrhyRes thmi could2014; ires testi ythmia is chara is a prote fam C etic pathoge counsel et al., 2010; Hu et al., for this inhsome families (Sotoodehnia et al., tic been suggested y of whic be conSavio-Galimberti prehensive . ARV um ionspenetrance ng for based on ily genehas r ing is osome, fam sidered nic vari icula ent cells withventr The Com a syndromes. Man sium and calci this path the differentMost variants ily,conduction reco adjac in association defects to date are missense changes et ac desm reported ant in to cardiac and to dete (Stenson several 2014). ogenic between predisposingPati the cardi (BrS) isto prov mmended rmine the KCNH arrhythmi of sodium, potas ers. There are C) affec ents rome hments missense al.,ts2014).l attac Heterozygous pathogenicsynd variants in the gene have willing to also been reported in association the ide test if this inSCN10A 2 gen ventricle, ). Brugadawith ing for discuss the anica to) shar otherss V1-3 movement interaction partn opathy (ARV mech the right peripheral (lead which is characterized and burning pain invariant inde e, then targ otherdysfunction ides with painful iomy with e insmall-fiber and their by autonomic thmiaeand et al., 2000 neuropathy, at-risk implication on ECG eted test penden factors r dysplasia/card us tissu arrhythe tionHuang icgen ns and provand fibro samorph ; Nava etic s tachy fam distal extremities (Faber et al., 2012; et al., 2013). Pathogenic variants associated with painful neuropathy eleva r tly ectio of e 2014 ily mem this test co-segre ing for ant/ and hea segment ope, ventricula minergic polym vari ventricula cell-to-cell conn cement by fat ally ettoal.,result bers. report, gates gain of function (Huang et al., 2014). (McNappear ed byinST stress- condition lth data (despecifica can visi maintains death and repla cardiac death is characteriz ased risk for sync2014). Catechola pitated by identifie preci en yte is and lly is t al., incre S) genome et d for the risk by myoc thmia and sudd nel function nction thatsyndrome (LQT iated with connec privacy ; Brugada icular of recu chan ) to adv t.org. QT BrS is assoc ey et al., 2009 um channel dysfu rrence ope, ventr et al., tachyarrhy abnormal ion ance ). Long disease. i for sync calci ; Hedl by knowle caused tural heart ler et al., 2009 ed by cardiac ; Priori et al., 2002 increased risk et al., 2008; Prior dge and of struc with a may erg to con absence death (Fow T) is characteriz te et al., 2008 is associated , arrhythmi (Goldenb nect cardiac Fuen and structure tion to a cardiac lsen syndrome sudden r tachycardia (CPV ines (de la val on ECG normal heart predisposi ll and Lange-Nie ophy. QT inter ventricula se of catecholam iduals with ). Genetic on of the relea as Jerve ular dystr induced ed by prolongati ac death in indiv rg et al., 2014 disorder, such rome and musc cardi Tranebjae multisystemic Carvajal synd characteriza, and sudden s, 2015; se, of a disea s arrhythmi rs and Christiaanor may be part re rome, Naxo 2004; Alde isolated featu Tawil synd an , Andersenoccur as syndrome Timothy Gen Likely Pathogenic Variant Result A likely pathogenic result indicates the presence of genetic variant(s) in a specific gene for which there is significant, but not conclusive, evidence that the variant(s) causes a genetic disorder, or poses an increased risk for developing other diseases. With this type of result, medical management options and testing of family members are often similar to as previously described for a positive result. RESULTS / MANAGEMENT Variant of Uncertain Significance (VUS) Result A variant of uncertain significance (VUS) result indicates an inconclusive outcome of a genetic test. A VUS is a change in a gene for which the association with disease cannot be clearly established. The available information for the variant is either insufficient or conflicting, and it cannot be determined at this time whether the variant is associated with a specific genetic disorder or if the variant is an unrelated (benign) variant unrelated to the patient’s disorder. In the case of a VUS test result, all medical management recommendations should be based on clinical symptoms, and past personal and family history. Predictive genetic testing of family members for a VUS is not indicated. Nevertheless, in some circumstances, it can be useful to test other family members through our Variant Testing Program to gain more evidence about the variant itself and its possible association with disease. Over time, additional clinical evidence may be collected about certain VUS, which could ultimately lead to the reclassification of the variant and test result. 12 Negative Result A negative result indicates that the genetic test did not identify reportable, medically relevant variant(s) in any of the genes tested. Therefore, the cause for the patient’s disorder or family history remains unknown. Although the patient’s disorder may be caused by non-genetic factors, a negative genetic test result does not completely rule out an underlying genetic cause. For example, the patient’s disorder may be due to unidentified genetic changes in gene regions or genes not included in the initial test. Depending on the patient’s personal and family health history, additional genetic testing may be indicated for the patient or another family member. A genetic specialist or other health care providers can determine if further genetic testing is appropriate. In case of a negative genetic test result, all medical management recommendations should be based on clinical symptoms in addition to past personal and family history. Predictive genetic testing of family members is not available. When an individual tests negative for a familial pathogenic variant that was previously identified in another affected family member, this is considered a ‘true’ negative test result. In most cases, this means that the individual has no greater risk for developing the specific genetic disorder that runs in the family than anyone in the general population. GUIDE FOR INHERITED ARRHYTHMIA 13 Medical Management Based on Genetic Test Results There are a variety of screening and management strategies available to patients with inherited arrhythmias. A specific patient’s management plan should be personalized and based on his or her genetic test result (type of arrhythmia and in some cases, specific genotype), as well as their personal and family health histories. The table below gives a general overview of some types of medical management and surveillance options available to patients with inherited arrhythmias, but is not meant to be all inclusive. Recommendation General Recommendations Category Lifestyle Modification • Depending on diagnosis, avoidance of competitive sports may be recommended.20 Additional known arrhythmogenic triggers, such as exercise (especially in LQT1 patients) and alarm clocks (in LQT2 patients) should be avoided. • Affected patients should undergo follow-up as recommended by their doctor.19-21 Screening Medications • At-risk family members should undergo screening, which typically involves an ECG and Holter monitor evaluation and may also include echocardiogram, stress testing and cardiac MRI. 21-24 • A variety of medications can be used to control symptoms and prevent arrhythmias depending on the specific diagnosis. These medications include: beta- blockers, calcium channel blockers, digoxin, verapamil, diuretics and anti-arrhythmics. • Certain medications should also be avoided, depending on diagnosis. • Brugada Drugs to Avoid: www.brugadadrugs.org • Long QT Drugs to Avoid: crediblemeds.org Procedures/Surgery • Ablation or cardioversion may be considered. Implanted Devices • Published guidelines exist discussing ICD/pacemaker placement for patients with arrhythmia. Family Planning/ Pregnancy • Patients should discuss family planning decisions with their doctor prior to attempting a pregnancy. In those cases where pregnancy is desired, a careful review of medications prior to pregnancy for potential teratogenic effects, recurrence risk and determination of how a patient will be followed during pregnancy is recommended. 14 Implications for Family Members Regardless of the result, patients should share their test report with their blood relatives, who can then discuss the results with their health care providers. Sharing a copy of the test result with family members and health care providers will help to determine if additional testing is necessary and will ensure that the proper test is ordered for relatives, if indicated. Most of the genes associated with inherited arrhythmias are associated with autosomal dominant inheritance, which means that only one pathogenic variant is required to cause disease. With positive or likely pathogenic test results in genes associated with autosomal dominant inheritance, first-degree relatives (including parents, siblings, and children) have a 50% chance to have the same variant. The risk for other family members to carry the variant depends on how closely related they are to the person with a positive or likely pathogenic test result. However, it is important to remember that for most of these genes, not all people who inherit a pathogenic or likely pathogenic variant will experience arrhythmia-related cardiac events due to reduced penetrance. In rare instances, some types of inherited arrhythmias are associated with autosomal recessive inheritance, such as with the CASQ2 and TRDN genes. With autosomal recessive inheritance, two pathogenic variants are required to cause disease, where one pathogenic variant is almost always inherited from each parent. The recurrence risk for two carriers of an autosomal recessive condition to have an affected child is 25%. KEY INFORMATION GUIDE FOR INHERITED ARRHYTHMIA 15 Genetic Counseling Prior to genetic testing, patients should speak with their health care provider and/or a genetics specialist about their personal and family health history. Health care providers should discuss the benefits and limitations of testing, as well as possible test results. These conversations help to determine if the patient is an appropriate candidate for testing, facilitate the ordering of appropriate test(s) and ensure that the patient has agreed to the proposed genetic testing (written informed consent). If pathogenic variant(s) have already been identified in a family member, testing of the specific variant(s) is appropriate. If no pathogenic variant(s) are known in a family with a specific genetic disorder, an affected family member with the highest likelihood of a positive test outcome (an individual manifesting associated clinical symptoms) is ideally the best person for initial testing within a family. In instances when an affected family member is not available, testing of an unaffected family member may be considered, although a negative test result will not guarantee that the unaffected individual does not have an increased risk to develop the clinical symptoms that are present in the family. KEY INFORMATION Once a patient makes the decision to undergo genetic testing, post-test genetic counseling is recommended to understand the implications of the results, including a discussion of the appropriate medical management based on both the test results and the patient’s medical and family history. Genetic counseling services across the country can be found at www.nsgc.org 16 Insurance Coverage and Cost for Genetic Testing GeneDx accepts all commercial insurance plans and is a Medicare provider. Additionally, GeneDx is a registered provider with several Medicaid plans. If a patient does not have health insurance coverage or cannot afford to pay the cost of testing, GeneDx offers a financial assistance program to help ensure that all patients have access to medically necessary genetic testing. For more information on the paperwork that is required by some insurance carriers, as well as additional details on patient billing and our financial assistance program, please visit our website: www.genedx.com/billing Genetic Information Nondiscrimation Act The Genetic Information Nondiscrimination Act of 2008, also referred to as GINA, is a federal law that protects Americans from discrimination by health insurance companies and employers based on their genetic information. However, this law does not cover life insurance, disability insurance, or long-term care insurance. GINA’s employment protections do not extend to individuals in the U.S. military, federal employees, Veterans Health Administration and Indian Health Service. Some of these organizations may have internal policies to address genetic discrimination. For more information, please visit: http://genome.gov/10002328 GUIDE FOR INHERITED ARRHYTHMIA 17 Resources for Patients GeneReviews ARVC: www.ncbi.nlm.nih.gov/books/NBK1131/ Brugada: www.ncbi.nlm.nih.gov/books/NBK1517/ CPVT: www.ncbi.nlm.nih.gov/books/NBK1289/ Long QT: www.ncbi.nlm.nih.gov/books/NBK1129/ National Institutes of Health Genetics Home Reference (NIH/GHR) ARVC: ghr.nlm.nih.gov/condition/arrhythmogenic-rightventricular-cardiomyopathy Brugada: ghr.nlm.nih.gov/condition/brugada-syndrome CPVT: ghr.nlm.nih.gov/condition/catecholaminergicpolymorphic-ventricular-tachycardia Long QT: ghr.nlm.nih.gov/condition/romano-ward-syndrome Short QT: ghr.nlm.nih.gov/condition/short-qt-syndrome National Heart Lung and Blood Association: www.nhlbi.nih.gov/health/health-topics/topics/arr Patient Support Organizations Sudden Arrhythmia Death Syndrome (SADS) Foundation: www.sads.org The Canadian Sudden Arrhythmia Death Syndromes (SADS) Foundation: www.sads.ca Sudden Cardiac Arrest Association: www.suddencardiacarrest.org Ramon Brugada Senior Foundation: www.brugada.org 18 References 1. McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia / cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J. 1994: 71: 215-8 (PubMed: 8142187). 2. Marcus FI et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: Proposed modification of the Task Force Criteria. Eur Heart J. 31:806-814, 2010 (PubMed: 20172912). 3. Lubitz SA, Yin X, Fontes JD, et al. Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA 2010;304:2263–2269. 4. Arnar DO, Thorvaldsson S, Manolio TA, et al. Familial aggregation of atrial fibrillation in Iceland. Eur Heart J 2006;27:708 –712. 5. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome. Report of the Second Consensus Conference. Heart Rhythm 2005;2:429–440. 6. Probst V, Kyndt F, Potet F, et al. Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenegre disease. J Am Coll Cardiol 2003;41:643–652. 7. Brink AJ, Torrington M. Progressive familial heart block—two types. S Afr Med J 1977;52:53–59. 8. Krahn AD, Gollob M, Yee R, Gula LJ, Skanes AC, Walker BD, Klein GJ. Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion. Circulation. 2005 Oct 11;112(15):2228-34. Epub 2005 Oct 3. 9. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluationof congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation 2006;113:1385–1392 10.Takenaka K, Ai T, Shimizu W, et al. Exercise stress test amplifies genotype phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation 2003;107:838–844. 11.Shimizu W, Noda T, Takaki H, et al. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome.Heart Rhythm 2004;1:276 –283. 12.Krahn AD, Gollob M, Yee R, et al. Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion. Circulation 2005;112:2228 –2234. 13.Viskin S, Postema PG, Bhuiyan ZA, et al. The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol 2010;55:1955–1961. 14.Funada A, Hayashi K, Hidekazu I, et al. Assessment of QT-intervals and prevalence of Short QT syndrome in Japan. Clin Cardiol 2008;31:270 –2749 15.Mason JW, Ramseth DJ, Chanter DO, et al. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects. J Electrocardiol 2007;40:228–234. 16.Kobza R, Roos M, Niggli B, et al. Prevalence of long and short QT in a young population of 41,767 predominantly male Swiss conscripts. Heart Rhythm 2009; 6:652– 657. 17.Wilde, A. A. M. & Behr, E. R. Genetic testing for inherited cardiac disease. Nat Rev Cardiol. 2013 Oct; 10(10): 571–83. GUIDE FOR INHERITED ARRHYTHMIA 19 18.NSGC Cardiovasular SIG Pocket Guide “Indications for referral to cardiovascular genetics.” http://www.nsgc.org/CardioGuide 19.HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm 2011 8(8):1308-1339. 20.Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A, Corrado D, Crosson JE, Deal BJ, Driscoll DJ, Estes NA 3rd, Araújo CG, Liang DH, Mitten MJ, Myerburg RJ, Pelliccia A, Thompson PD, Towbin JA, Van Camp SP; Working Groups of the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention; Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004 Jun 8;109(22):2807-16. Review. 21.Hershberger R, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline. J Card Fail. 2009 Mar; 15(2):83-97. 22.Oe et al. Prevalence and clinical course of the juveniles with Brugada-type ECG in Japanese population. Pacing Clin Electrophysiol. 2005 Jun;28(6):549-54. 23.Napolitano C, Priori SG and Bloise R. Catecholaminergic polymorphic ventricular tachycardia. GeneReviews. NCBI/NIH. Initial posting 2004, last update 2013. 24.24. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol 2006; 48:e247-e346. 20 Notes GUIDE FOR INHERITED ARRHYTHMIA 21 About GeneDx GeneDx was founded in 2000 by two scientists from the National Institutes of Health (NIH) to address the needs of patients diagnosed with rare disorders and the clinicians treating these conditions. Today, GeneDx has grown into a global industry leader in genomics, having provided testing to patients and their families in over 55 countries. Led by its world-renowned whole exome sequencing program, and an unparalleled comprehensive genetic testing menu, GeneDx has a continued expertise in rare and ultra-rare disorders. Additionally, GeneDx also offers a number of other genetic testing services, including: diagnostic testing for hereditary cancers, cardiac, mitochondrial, and neurological disorders, prenatal diagnostics, and targeted variant testing. At GeneDx, our technical services are backed by our unmatched scientific expertise and our superior customer support. Our growing staff includes more than 30 geneticists and 100 genetic counselors specializing in clinical genetics, molecular genetics, metabolic genetics, and cytogenetics who are just a phone call or email away to assist you with your questions and testing needs. We invite you to visit our website: www.genedx.com to learn more about us. 207 Perry Parkway Gaithersburg, MD 20877 T 1 888 729 1206 (Toll-free), 1 301 519 2100 • F 1 201 421 2010 E [email protected] • www.genedx.com © 2016 GeneDx. All rights reserved. 40164 V1 11/16 Information current as of 11/16