Guia_4333 Diagnostico Enf.cardiacas Geneticas

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Review

Guidelines for Genetic Testing of Inherited CardiacDisorders

Jodie Ingles, BBiomedSci, GradDipGenCounsa,b,1, Poonam R. Zodgekar, MSW,GradDipGenCounsc,1, LauraYeates, BSc(Hons), GradDipGenCounsa, Ivan Macciocca,

BSc, GradDipGenCounsd, Christopher Semsarian, MB BS, PhD, FRACP, FAHA,FCSANZ a,b and Diane Fatkin, MD, FRACP, FCSANZc,e,, members of the CSANZ

Cardiac Genetic Diseases Council Writing Groupa Agnes Ginges Centrefor Molecular Cardiology, CentenaryInstitute, Camperdown, New South Wales, Australia

b SydneyMedical School, University of Sydney, andDepartment of Cardiology, Royal PrinceAlfredHospital, Camperdown, New South Wales,Australia

c Molecular Cardiology and Biophysics Division, Victor ChangCardiac ResearchInstitute, Darlinghurst, New South Wales, Australiad Genetic HealthServices Victoria, Royal ChildrensHospital, andMurdoch ChildrensResearchInstitute, Parkville, Victoria, Australia

e Cardiology Department, StVincents Hospital, Darlinghurst, andFaculty of Medicine, University of New South Wales, Kensington, New SouthWales, Australia

Inherited gene variants have been implicated increasingly in cardiac disorders but the clinical impact of these dis-coveries has been variable. For some disorders, such as familial hypertrophic cardiomyopathy, long QT syndrome, andfamilial hypercholesterolaemia, genetic testing has a highyield and has become an integral part of family management.For other disorders, including dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Brugada syn-drome, catecholaminergic polymorphic ventricular tachycardia, and atrial fibrillation, relatively less is known aboutthe genes involved and genetic testing has a lower yield. Recent advances in sequencing and array-based technologiespromise to change the landscape of our understanding of the genetic basis of human disease and will dramaticallyincrease the rate of detection of genomic variants. Since every individual is expected to harbour thousands of vari-ants, many of which may be novel, interpretation of the functional significance of any single variant is critical, andshould be undertaken by experienced personnel. Genotype results can have a wide range of medical and psychosocialimplications for affected and unaffected individuals and hence, genetic testing should be performed in a specialisedcardiac genetic clinic or clinical genetics service where appropriate family management and genetic counselling can beoffered.

(Heart, Lung and Circulation 2011;20:681687) 2011 AustralasianSociety of Cardiac andThoracic Surgeons and theCardiac Society of Australia andNewZealand.

Publishedby Elsevier Inc. All rights reserved.

Keywords. Cardiovascular diseases; Genetic testing

Introduction

In recent years, there has been increasing recognitionof the importance of inherited gene mutations as acause of cardiomyopathies and arrhythmogenic disor-ders. Substantial progress has been made in elucidating

the molecular defects underpinning these diseases, butthe impact of these discoveries on clinical managementis often unclear. This document aims to outline the

Received 13 July 2011; accepted 22 July 2011

Corresponding author at: Victor Chang Cardiac ResearchInstitute, Lowy Packer Building, 405 Liverpool St, PO Box 699,Darlinghurst NSW 2010, Australia. Tel.: +61 2 9295 8618;fax: +61 2 9295 8601.

E-mail address:[email protected] (D. Fatkin).1 These authors contributed equally to this work.

current status ofgenetic testing for a range of inheritedcardiac disorders in order to provide cardiologists andother health professionals with a clear understanding ofthe process, including the advantages and limitations oftesting.

Indications for Genetic Testing

There are a number of inherited cardiac disorders forwhich genetic causes have been identified, includinghypertrophic cardiomyopathy (HCM), dilated cardiomy-opathy (DCM), arrhythmogenic right ventricular car-diomyopathy (ARVC), left ventricular non-compaction,restrictive cardiomyopathy, long QT syndrome (LQTS),Brugada syndrome (BrS), catecholaminergic polymor-phic ventricular tachycardia (CPVT) and atrial fibrillation.

2011 Australasian Society ofCardiac and Thoracic Surgeons and the Cardiac Society ofAustralia and New Zealand. Published by Elsevier Inc. All rights reserved.

1443-9506/04/$36.00doi:10.1016/j.hlc.2011.07.013
mailto:[email protected]://dx.doi.org/10.1016/j.hlc.2011.07.013http://dx.doi.org/10.1016/j.hlc.2011.07.013mailto:[email protected]


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682 Ingles et al. Heart, Lung and CirculationCardiac Genetic Testing 2011;20:681687

Genetic testing is also indicated in some multisystem dis-orders with frequent cardiovascular involvement, suchas familial hypercholesterolaemia (FH) and Marfan syn-drome (MS). Genetic testing for HCM, LQTS, and FH hasbecome an integralpart ofclinical management [1,2], how-ever, genetic testing is not so straightforward for many of

the other conditions.Genetic testing is the process ofsearching through theDNA sequence of disease-associated genes to identifya sequence variation that is pathogenic (mutation). Ingeneral, genetic testing is considered when an individ-ual has a clinical diagnosis ofan inherited heart disease,particularly if there is a positive family history. Initialgenetic testing to identify a causative mutation is ide-ally offered to a member ofthe family who has definiteclinical disease to maximise the chance of detecting amutation. In cases where the only known affected indi-vidual is deceased there may be the option of testingpost-mortem blood/tissue samples or Guthrie card, how-ever, the quality ofDNA being tested is often diminishedmaking this technically challenging. It is now well estab-lished that a small proportion offamilies have more thanone disease-causing mutation in either different alleles ofthe same gene or in different genes. This phenomenonis most widely reported in HCM, LQTS and ARVC [39].Therefore, it is recommended that for these conditions,the search for the family specific mutation in the indexcase should not cease once a mutation is identified, butshould continue to include all of the common genesassociated with the condition. This also highlights theadvantages oftesting large gene panels rather than singlegenes.

Availability of Genetic Testing

Genetic testing for inherited cardiac disorders is availablethrough clinical genetics services throughout Australia. Asmall number ofspecialised cardiac genetic clinics oper-ate in major centres including Sydney, Melbourne andBrisbane and these comprise a multidisciplinary teamof cardiologists, clinical geneticists and genetic counsel-lors/coordinators [10]. Some DNA testing is performedwithin Australian laboratories, however testing for manyconditions requires sending samples to overseas labora-tories (see Appendix A).

Several factors can impact on the availability and utilityofgenetic testing, such as access to testing, cost oftestingandthe mutation detection rate. These factors vary greatlydepending on the disease (see Table 1), with genetic test-

ing for HCM, LQTS, and FH being readily available andhaving a relatively high probability (up to 75%) offindinga mutation. For other conditions such as DCM, there isa low yield ofmutations found overall. However, muta-tion screening of the LMNA gene is worthwhile in thesubset offamilies with DCM and conduction-system dis-ease [11,12]. For other families with DCM, participation inresearch studies investigating new candidate genes couldbe considered as an option.

Families with a diagnosis ofan inherited heart diseaseshould be referred to either their local clinical genetics

service, or one ofthe major cardiac genetic clinics. Healthprofessionalswho coordinateandmanage these clinicsareup-to-date with thelaboratories offering the most compet-itive service and price, and are able to offer appropriategenetic counselling. Genetic testing performed by com-mercial laboratories does not yet attract any Medicare

rebate. Reimbursement ofcosts may be covered in someareas byclinical genetics or cardiology services, or chargedto family members and needs to be explored on an indi-vidual basis. Cost recovery for genetic testing is a subjectofongoing discussionand rebates for thisservice are likelyto be available in the future.

Interpretation of Genetic Test Results

There are several possible outcomes ofthe initial genetictesting performed in the affected member of a family.Firstly, a potential disease-causing mutation may be iden-tified. With recent technological advances that enablehigh-throughput sequencing of multiple genes, a largenumber ofsequence variantsmay be found in this individ-uals DNA sample. The majority of these are likely to bemissense (that is, a single base pair substitution resultingin a change in amino acid), and there may be a numberof novel variants. It is common practice for laboratoriesto report all variants found in genetic testing, includingnovel and previously reported variants. A number ofcri-teria are used to support a variant as being potentiallydisease-causing, including segregationwith disease statusin other affected family members, absence from a con-trol population, and location in a conserved amino acidsequence [13]. Evidence of altered gene function is ide-ally required to confirm pathogenicity, however, this typeofsupporting evidence is frequently not available. Othertypes ofmutations, for example, those that lead to short-

ened (truncated) gene products or involvingdeletions andduplications oflarge segments ofa gene, are generally eas-ier to classify as pathogenic. A number ofnew techniquesare now available for detection ofthese copy number vari-ations. Careful evaluation ofdata obtained from genetictestingisrequiredto avoid giving misleading andincorrectgenetic results. Interpretation of DNA sequence resultsshould be undertaken by experienced personnel, includ-ing molecular geneticists, molecular cardiologists, clinicalgeneticists, and/or genetic counsellors.

Another common outcome of genetic testing is that asequence variation ofunknown significance may be iden-tified. These are variations in the DNA for which thereis not enough evidence to clearly categorise the vari-

ant as disease-causing. When a variation of unknownsignificance is identified, its utility in confirming the diag-nosis in a proband with suspected disease is limited andit cannot be used for predictive gene testing in at-riskrelatives.

Finally, in a large number offamilies, no mutation maybe identified. There could be several explanations for this.It is possible that the disease-causing mutation in thefam-ilyis present in a gene that was not tested, orina gene thatis yet to be discovered. Alternatively, it is possible thatthere is a mutation in one of the genes that was tested,


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Heart, Lung and Circulation Ingles et al. 6832011;20:681687 Cardiac Genetic Testing

Table 1. Overview of CurrentlyAvailable Genetic Testing inInheritedHeartDisease.

Disease Genes Tested Detection Ratea ApproximateCosta (AUD)

Ref.

HCM MYH7,MYBPC3, TNNT2, TNNI3, TPM1,MYL2,MYL3,ACTC1, CSRP3b

4060% $2000$3500 [11]

DCM Various combinations of:ABCC9,ACTC,ACTN2,ANKRD1, CSRP3, CTF1, DES, DSG2,DSP, EMD, LDB3, LMNA,MYBPC3,MYH7,PLN, SCN5A, SGCD, TAZ, TCAP, TNNC1,TNNT2, TNNI3, TPM1, VCL.


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treatment and lifestyle modification, as appropriate [20].For most inherited cardiac diseases, however, given theremay be significant intra-familial phenotypic variation,there is still a lot of uncertainty regarding age of onset,progression ofdisease and benefits ofprophylactic treat-ment.

A negative result, on the other hand, can provide reas-surance and eliminates the need for cardiac follow-up.In the event of a new onset of symptoms, the possibil-ity ofan additional cause ofdisease in the family shouldbe considered. Receiving a negative test result may alsogenerate an emotional reaction, such as guilt, particularlyin families where other siblings are affected or mutation-positive. Ongoing counselling follow-up, either with agenetic counsellor or through another qualified counsel-lor, should be offered where required.

Genetic Testing in Children

Predictive genetic testing in children is likewise a complex

issue, and is managed on a case-by-case basis, and varieswith the condition for which predictive testing is beingrequested.

The Human Genetics Society ofAustralasia guidelineson predictive genetic in children and adolescents statethatwhen there is medical benefit in the immediate futuregenetic testing should be offered [21]. Whilst cardiovascu-lar genetic diseases may fit these criteria particularly withregard to avoiding high-level sports for the riskofsuddendeath, consideration must be made in view of the childand their current and future autonomy. For the majorityofpatients at riskofa familial cardiomyopathy, consider-ation should be given to delaying testing to give the childan opportunity to have some understanding of the test

and the implications ofits result. This is generally fromthe early to mid-teens as this coincides with the periodofonset ofdisease when regular clinical screening beginsfor most cardiomyopathies. For inherited arrhythmia syn-dromes, predictive testing may be performed earlier inlife given that sudden death can occur at any age and formost ofthese syndromes, for example, LQTS and CPVT,prophylactic therapy may be initiated. Genetic testing ofminors may include assessment by a child mental healthspecialist to ensure that a genetic result will not adverselyaffect the well being ofthe child.

Prenatal Testing

Ifa disease-causing mutation is known in the family, thisinformation can be used for future/current pregnancies.In established pregnancies, genetic testing offoetal DNAvia chorionic villus sampling (1012 weeks gestation) oramniocentesis (1518 weeks gestation) can determine ifthe foetus carries the disease-causing gene, and thereforemay develop disease inthe future. Ifparents receive a pos-itive result they can choose whether or not to continue withthe pregnancy. A couple wishing to consider pre-nataldiagnosis should be referred to their local genetics unitwith experience in genetic testing in pregnancy. Pre-natal

diagnosis is not available in families where the causativemutation is not known.

Pre-implantation genetic diagnosis (PGD) is a methodusing in vitro fertilisation (IVF) technologies, whereembryos are testedfor thepresence ofthe disease-causingmutation. Only those embryos without the mutation

are implanted. Pre-implantation genetic diagnosis is anexpensive technology, as each familys mutation needs tobe workedupbytheservice before beginning IVF. Familieswho are interested in pursuing PGD should be referred toan appropriate local IVF provider, who will discuss withthem the process, cost and success rates.

Implications for Patient Management

In most cases, the presence ofa mutation on genetic test-ing result will not alter the clinical management of anindividual who is already known to be affected. How-ever, in cases where an unaffected individual receives apositive predictive gene test result, an ongoing surveil-lance program should be recommended. Due to variableage of onset, surveillance should be started early, andmay be determined by the natural history in the fam-ily. Genotypephenotype correlations, ifknown, could bean important consideration in determining screening forasymptomatic mutation positive individuals. In some con-ditions, such as HCM, ARVC or CPVT, a positive familyhistory of sudden death, may lower the threshold forpreventive implantation ofan automated implantable car-dioverter defibrillator (AICD) [20].

Pregnancy management of women with a positivegenetic test result is an important consideration. Foraffected women, who are undergoing pharmacologicaltreatment, and contemplating pregnancy, a specialistreview is recommended. An evaluation of the benefits

and harms ofcessation ofmedication is needed, or alter-natively, consideration of drugs that will minimise thechances ofan unsuccessful pregnancy. During pregnancy,there is a needfor regular cardiac evaluation,as pregnancymay worsen the condition for an already affected individ-ual, or may even unmaskdisease in an as yet unaffectedindividual, and result in early presentation [22].

Implications for Lifestyle Recommendations

Mutation-positive individuals should receive appropriatelifestyle modification advice as part of result follow-up. Strenuous competitive sporting activities should beavoided in individuals with inherited cardiac disorders

[23]. Informationshould be provided to highlight the dele-terious effects of alcohol excess, as well as arrhythmictriggers such as recreational drugs. Cessation ofsmokingis generally recommended, and is particularly importantin families with FH.

Conclusion

Genetic testing for inherited cardiac disorders has seenmajor advancements in recent years. Several factors suchas access, cost, utility and yield of testing should be


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considered when offering genetic testing for a particularcondition.

In summary, we make the following who-to-test rec-ommendations:

Genetic testing should be discussed with all clini-

cally affected probands who have the inherited heartdiseases outlined in this document. Probands andreferring physicians should have realistic expecta-tions about the likely yield oftesting, which currentlyranges from high, as is the case for HCM, LQTS,FH, and CPVT, to relatively low (e.g. DCM). Genetictesting should be performed in the setting of aspecialised cardiac genetic clinic or clinical geneticsservice where appropriate genetic counselling can beoffered.

Asymptomatic first-degree family members shouldattend a specialised cardiac genetic clinic or their localcardiologist for periodic clinical screening as per cur-rent guidelines. Ifa likely pathogenic gene variation is

identifiedin a family proband, symptomatic and asymp-tomatic family members should be informed about thepossibility of genetic testing and appropriate geneticcounselling provided.

Although genetic testing plays an importantrole in fam-ily management, genetic test results should not be used asa surrogate for careful clinical evaluation offamily mem-bers, which remains the primary basis for a diagnosisof inherited heart disease. Detailed phenotype evalua-tion and genotypephenotype correlations may help todetermine which patients are most likely to benefit andwhich genes are likely to have the highest yield fortesting. Clinical genetic services and specialist cardiac

genetic clinics around Australia are best-equipped tosee patients and discuss these issues as well as impor-tant psychosocial considerations prior to commencinggenetic testing. For those conditions for which relativelyless is known about the genetic causes ofdisease, par-ticipation in genetics research programs is a worthwhileoption and should be encouraged. The introduction ofnew technologies for mutation detection,such as genome-wide sequencing promises to rapidly increase the rateof variant detection and should enable more families toacquire genotype results. However, this will bring newchallenges for sequence variant interpretation and manyvariants ofuncertain significance are likely to be found.As this is a rapidly expanding field, recommendations

for genetic testing will change considerably over the nextfew years and we encourage readers to consult withtheir local cardiac genetic service for the most up-to-dateinformation.

Acknowledgment

D. Fatkin was supported by an NHMRC Senior ResearchFellowship (404808).Jodie Ingles is the recipient ofa Uni-versity ofSydney Postgraduate Award.

Appendix A. Useful Contacts

AUSTRALIAREGISTRYNational Genetic Heart Disease Registry.Coordinator: Ms Jodie Ingles.Contact:Jodie +61 2 9565 6185.

BRISBANECardiac Genetics Clinic, Royal Brisbane & Womens

Hospital, A/Prof.John Atherton, A/Prof.Julie McGaugh-ran.

Contact: +61 7 3636 1686; [email protected].

SYDNEYHypertrophic Cardiomyopathy Clinic & Genetic Heart

Disease Clinic, Royal Prince Alfred Hospital, Prof. ChrisSemsarian, Ms LauraYeates.

Contact: Laura +61 2 9565 6187; [email protected].

Cardiac Genetic Clinic, Liverpool Hospital, Prof. JohnFrench, Prof. David Sullivan, clinical geneticists/genetic

counsellors.Contact: Prof. French +61 2 9828 4655; j.french@unsw.

edu.au.Sr Bernice Research Program In Inherited Heart Dis-

eases, Victor Chang Cardiac Research Institute, A/Prof.Diane Fatkin.

Contact: A/Prof. Fatkin +61 2 9295 8618;[email protected].

Familial Hypercholesterolaemia and High Cardiovas-cular Disease Risk Family Clinic, Royal Prince AlfredHospital, A/Prof. David Sullivan,

Contact: Lucinda Freeman +61 2 9515 5062;[email protected].

MELBOURNE

Cardiomyopathy Clinic & Arrhythmia Clinic (Paedi-atrics), Royal Childrens Hospital, Melbourne, Dr AndrewDavis, Dr Robert Weintraub, Dr Andreas Pflaumer, MsVanessa Connell.

Contact:Vanessa +61 3 9345 4239; [email protected].

Cardiac Genetics Clinic, Royal Melbourne Hospital,Prof. Ingrid Winship, A/Prof. Jitendra Vohra, Dr LesleyAdes, Ms Tina Thompson, Mr Ivan Macciocca.

Contact: Ivan +61 3 8341 6373 or Tina +61 3 9342 7151;[email protected].

Cardiac Genetics Clinic, Monash Medical Centre, DrPaulJames, Mr Ivan Macciocca.

Contact: Ivan +61 3 8341 6373; ivan.macciocca@ghsv.

org.au.Inherited Cardiomyopathy/Arrhythmia Genetic Coun-

selling Service, Genetic Health Services Victoria, Mur-doch Childrens Research Institute, Royal ChildrensHospital.

Contact: Ivan +61 3 8341 6373; [email protected].

WESTERNAUSTRALIALipid Disorders Clinic, Royal Perth Hospital, Perth,

Winthrop Professor Gerald F Watts, Ms Lynda Southwell.
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


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Contact: Prof. Watts +61 8 9224 0245; [email protected], or Linda, +61 8 9224 8092, [email protected], or [email protected] .

Cardiovascular Genetics Laboratory, Royal Perth Hos-pital, Perth, Professor F van Bockxmeer,

Contact: Prof. Bockxmeer +61 8 9224 2322;

[email protected] .FH Patient Support Group:www.familialhypercholesterolaemiasupportwa.websyte.com.au

Contact: Kristina Sengotta +61 8 9389 6722;[email protected],www.geneticsupportcouncil.org.au.

NEWZEALANDCardiac Inherited Disease Group(CIDG),www.cidg.org

A/Prof.Jon Skinner, Ms Jackie Crawford,Contact: Jackie: +64 9 3074949 ext 23634;

[email protected] list ofclinical genetics services throughout Australia

and New Zealand can be found at www.genetics.com.au.

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