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Vol. 39. Issue 10.
Pages 597-610 (October 2020)
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Vol. 39. Issue 10.
Pages 597-610 (October 2020)
Review Article
DOI: 10.1016/j.repce.2020.03.008
Open Access
Recommendations for genetic testing in cardiology: Review of major international guidelines
Recomendações para a realização de testes genéticos em cardiologia – revisão das principais diretrizes internacionais
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Alexandra Sousaa,b,c,
Corresponding author
xanasousa81@gmail.com

Corresponding author.
, Oana Moldovand, Ana Lebreiroe, Mafalda Bourbonf, Natália Antóniog,h, Quitéria Ratoi, Patrícia Rodriguesj, Alexandra Tostek, Miguel Gonçalves Rochal, Renata Oliveiram, Sofia Granjan, Cristina Cruza,e, Jorge Almeidao, Elisabete Martinsa,e,p
a Departamento de Medicina, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
b CINTESIS, Cardiocare – Centro de Investigação em Tecnologias e Serviços de Saúde, Porto, Portugal
c Serviço de Cardiologia, Hospital de Santa Maria Maior, Barcelos, Portugal
d Departamento da Criança e da Família, Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal
e Serviço de Cardiologia, Centro Hospitalar Universitário de São João, Porto, Portugal
f Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal
g Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal
h Serviço de Cardiologia, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
i Serviço de Cardiologia, Centro Hospitalar de Setúbal, Setúbal, Portugal
j Serviço de Cardiologia, Centro Hospitalar Universitário do Porto, Porto, Portugal
k Hospital da Luz, Lisboa, Portugal
l Unidade de Genética Médica, Hospital de Braga, Braga, Portugal
m Serviço de Genética Humana, Centro Hospitalar Universitário de São João, Porto, Portugal
n Serviço de Cardiologia Pediátrica, Centro Hospitalar Universitário de São João, Porto, Portugal
o Serviço de Cirurgia Cardiotorácica, Centro Hospitalar Universitário de São João, Porto, Portugal
p i3S – Instituto de Investigação e Inovação em Saúde, Porto, Portugal
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Tables (2)
Table 1. Recommendations for genetic testing in channelopathies.
Table 2. Recommendations for genetic testing in cardiomyopathies.
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Abstract

In recent years, the importance of genetic causes of cardiovascular diseases has been increasingly recognized, as the result of significant advances in molecular diagnosis techniques. This growing knowledge has enabled the identification of new phenotypes and the subclassification of clinical syndromes, impacting the therapeutic approach and genetic counseling offered to affected families.

This paper describes the state of the art of genetic testing in the main cardiovascular diseases, aiming to provide a useful tool to help cardiologists and other health professionals involved in the care of individuals with hereditary heart diseases and their families.

Keywords:
Inherited cardiovascular diseases
Genetic testing
Resumo

Nos últimos anos, tem sido crescente o reconhecimento das causas genéticas das doenças cardiovasculares resultante dos significativos progressos das técnicas laboratoriais. Este conhecimento tem permitido a identificação de «novos» fenótipos e a subclassificação das síndromes clínicas, tendo impacto nas decisões terapêuticas e no aconselhamento genético que é facultado às famílias.

No presente documento descreve-se o «estado da arte» relativamente às principais recomendações para testes genéticos nas doenças cardiovasculares, pretendendo-se providenciar uma ferramenta útil de consulta para Cardiologistas e outros Profissionais envolvidos na prestação nos cuidados de saúde a doentes com cardiopatias hereditárias e respetivas famílias.

Palavras-chave:
Doenças cardiovasculares hereditárias
Testes genéticos
Full Text
Introduction

In recent years, the importance of genetic causes of cardiovascular diseases has been increasingly recognized, and technical advances have enabled many of the underlying molecular mechanisms to be understood in detail.

The great strides in genetic sequencing, especially next-generation sequencing, have increased the range of molecular diagnosis, but in many cases this has resulted in the detection of genetic variations of as yet uncertain significance, which complicates genetic counseling for patients and their relatives. It is thus essential for cardiologists and other health professionals involved in the care of individuals with hereditary heart diseases and their families to be familiar with the indications, advantages and limitations of genetic tests.

This document describes the main indications for genetic testing in the most important inherited cardiovascular syndromes and diseases and for postmortem genetic testing.

General recommendations

Whenever appropriate, physicians should inform their patients about the mechanisms of the hereditary disease in question and the implications for their relatives, and refer them for a medical genetics consultation.

Genetic counseling should take place both before and after genetic testing, in order to ensure that patients understand the benefits and limitations of the results, and only after patients have provided informed consent. Results should be communicated only to the patient him- or herself.

Children

Genetic testing should be requested for children only if it can be of immediate benefit to them and with the informed consent of their parents or guardians. Tests that would reveal a disease that usually has onset in adulthood and for which there is no proven prevention or cure should not be requested. Whenever appropriate, the child should be involved in the process according to his or her degree of autonomy.

Presymptomatic tests

Presymptomatic tests are defined as those that can identify a currently asymptomatic individual as a carrier of a genetic variant that is unequivocally associated with a pathological condition. In healthy individuals, presymptomatic tests should only be performed in the context of a medical genetics consultation, following genetic counseling and provision of written informed consent. The results should only be communicated to the patient him- or herself and not to third parties, including physicians not directly involved in the testing process, without written authorization.

Genetic testing in Portugal is regulated by Decree-Law 12/2005, the relevant parts of which are presented in Supplement 1.

The main genetic tests used in clinical practice, the genes referred to, and abbreviations used in this document, are listed in Supplements 2-4, respectively.

Classification of genetic variants

Genetic variants should be classified as one of five categories: pathogenic, likely pathogenic, of uncertain significance, likely benign, or benign.1 Only pathogenic or likely pathogenic variants should be used to direct specialized follow-up and to prompt genetic study of an at-risk carrier and asymptomatic relatives.

Classes of recommendation and levels of evidence

Most of the information available is derived from registries and non-randomized studies and is thus level of evidence C. The classes of recommendation and levels of evidence used in this document are presented in Supplement 5.

Genetic testing in relatives

When a pathogenic or likely pathogenic genetic variant is identified in an index case, it is a class I recommendation,2,3 as with all hereditary heart diseases, to perform genetic testing in relatives, together with genetic counseling both before and after testing.

Channelopathies

Channelopathies are primary electrical diseases of the heart that are not accompanied by macroscopic or histopathological abnormalities detectable by conventional means, since the functional and structural alterations occur at the molecular level, in the cell membrane.4 They constitute a varied group of diseases in which pathogenic variants in genes that code for ion channels cause changes in the ion currents involved in the action potential of cardiac cells, leading to potentially fatal arrhythmias.5,6

J-wave syndromes

J-wave syndromes are those in which an elevated J wave (appearing as a J point) on the electrocardiogram (ECG) is associated with increased risk of ventricular arrhythmias.7 Among the best-known of these syndromes are Brugada syndrome (BrS) and early repolarization syndrome (ERS), which are associated with the development of polymorphic ventricular tachycardia (VT), ventricular fibrillation (VF) and sudden death (SD). J-wave/J-point abnormalities occur in different leads of the ECG in BrS (right precordial leads) and ERS (mainly in the inferior and lateral leads).7,8

Brugada syndromeClinical diagnosis

Diagnosis of BrS is made in the presence of a type 1 pattern on the ECG (coved-type ST-segment elevation of ≥2 mm in one or more of the right precordial leads, V1 and/or V2, in the second, third or fourth intercostal space), spontaneously or following provocation with a sodium channel blocker such as flecainide or ajmaline.8–10

To avoid overdiagnosis, when a type 1 pattern has been documented on the ECG only after pharmacological provocation, at least one of the following criteria should also be fulfilled for a diagnosis of BrS: VF or polymorphic VT; syncope of probable arrhythmic cause; family history of SD before the age of 45 years with negative autopsy; type 1 pattern in relatives; nocturnal agonal respiration; or inducibility of VT/VF.8 Table S1 in Supplement 6 presents a diagnostic score for BrS.8

Genetic diagnosis

BrS is associated with genetic variants in multiple genes, most of which code for sodium channels (SCN5A in 11-28% of probands, SCN10A in 5-17%) or calcium channels (CACNA1C in 7% and CACNB2b in 5%).8

Genetic testing is not necessary for the diagnosis, but can be useful in cases of doubtful phenotypes and in those with established BrS (class IIb3 or IIa2 recommendation), particularly to facilitate familial genetic screening (class IIb3) (Table 1).

Table 1.

Recommendations for genetic testing in channelopathies.

Disease  Recommendation  R-LE  Source (year) 
BrSComprehensive or BrS1 (SCN5A) targeted genetic testing can be useful for any patient in whom there is a clinical index of suspicion for BrS based on clinical history, family history, and electrocardiographic findings (resting 12-lead ECGs and/or provocative drug challenge testing).  IIa-C  HRS/EHRA (2011)2 
In patients with suspected or established BrS, genetic counseling and genetic testing may be useful to facilitate cascade screening of relatives.  IIb-C  AHA/ACC/HRS (2017)3 
Genetic testing is not indicated in the setting of an isolated type 2 or type 3 Brugada pattern.  III-C  HRS/EHRA (2011)3 
ERS  Genetic testing is not recommended.  III-B  AHA/ACC/HRS (2017)3 
LQTSComprehensive or LQTS 1-3 (KCNQ1, KCNH2, and SCN5A) targeted genetic testing is recommended for any asymptomatic patient with QTc >480 ms (prepuberty) or >500 ms (adults), in the absence of secondary causes.  I-C  HRS/EHRA (2011)3 
Comprehensive or LQTS 1-3 (KCNQ1, KCNH2, and SCN5A) targeted genetic testing is recommended for any patient in whom there is a strong clinical index of suspicion for LQTS based on clinical history, family history, and electrocardiographic findings (resting 12-lead ECGs and/or provocative stress testing with exercise or catecholamine infusion).I-C  HRS/EHRA (2011)3 
I-B  AHA/ACC/HRS (2017)3 
Comprehensive or LQTS 1-3 (KCNQ1, KCNH2, and SCN5A) targeted genetic testing may be considered for any asymptomatic patient with QTc >460 ms (prepuberty) or >480 ms (adults), in the absence of secondary causes.  IIb-C  HRS/EHRA (2011)3 
SQTSComprehensive or SQTS 1-3 (KCNH2, KCNQ1, and KCNJ2) targeted genetic testing may be considered for any patient in whom there is a strong clinical index of suspicion for SQTS based on clinical history, family history, and electrocardiographic phenotype.  IIb-C  HRS/EHRA (2011)3 
In patients with SQTS, genetic testing may be considered to facilitate screening of first-degree relatives.  IIb-C  AHA/ACC/HRS (2017)3 
CPVTComprehensive or CPVT1 and CVPT2 (RYR2 and CASQ2) targeted genetic testing is recommended for any patient in whom there is a clinical index of suspicion for CPVT based on clinical history, family history, and electrocardiographic findings during provocative stress testing with exercise or catecholamine infusion.  I-C  HRS/EHRA (2011)3 
In patients with CPVT and with clinical VT or exertional syncope, genetic testing is reasonable.  IIa-B  AHA/ACC/HRS (2017)3 

ACC: American College of Cardiology; AHA: American Heart Association; BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; ECG: electrocardiogram; EHRA: European Heart Rhythm Association; ERS: early repolarization syndrome; HRS: Heart Rhythm Society; LE: level of evidence; LSQTS: long QT syndrome; QTc: corrected QT interval; R: class of recommendation; SQTS: short QT syndrome; VT: ventricular tachycardia.

Early repolarization syndromeClinical diagnosis

Diagnosis of ERS is based on a pattern of early repolarization in the inferior and/or lateral leads and a history of aborted SD, documented VF or polymorphic VT.8 ER is recognized if (1) there is an end-QRS notch (J wave) or slur on the downslope of a prominent R wave with and without ST-segment elevation; (2) the peak of the notch or J wave (Jp) ≥0.1 mV in ≥2 contiguous leads of the 12-lead ECG, excluding leads V1-V3; and (3) QRS duration (measured in leads in which a notch or slur is absent) of <120 ms.11 Table S2 in Supplement 6 presents a diagnostic score for ERS.8

Genetic diagnosis

ERS has so far been associated with genetic variants in seven genes, mainly coding for calcium channels (CACNA1C, CACNB2b and CACNA2D1), but their etiological role is questionable8 and so genetic testing is not recommended3 (Table 1).

QT syndromesLong QT syndromeClinical diagnosis

The diagnosis of long QT syndrome (LQTS) is based on measurement of the QT interval after excluding secondary causes of QT prolongation such as drugs or electrolyte imbalances.10 To help with diagnosis, a score has been created12 that as well as corrected QT interval (QTc) also considers other electrocardiographic abnormalities, symptoms, and family history (Table S3, Supplement 6). The diagnosis is now established with either QTc ≥480 ms in repeated ECGs (class I) or LQTS risk score >3 (class I), or in the presence of a confirmed pathogenic LQTS mutation, irrespective of the QT duration (class I); it should be considered in the presence of QTc ≥460 ms in repeated 12-lead ECGs in patients with unexplained syncope.9

Genetic diagnosis

LQTS is associated with documented genetic variants in at least 15 genes.13 Genetic testing identifies pathogenic variants in around 75% of cases, and three genes are responsible for about 90% of positive tests: KCNQ1, KCNH2 and SCN5A (associated with types 1, 2 and 3 LQTS, respectively.9 Genetic testing is of particular value in these cases, since the three genotypes are associated with different degrees of SD risk, especially in association with gender and QTc duration (the risk is highest in women with type 2 LQTS and in men with type 3 LQTS and QTc >500 ms6,14), and since the triggers for arrhythmic events also differ (physical exertion, particularly swimming, in type 1; sudden loud noises in type 2; and rest or sleep in type 3).6,15 Around 20-25% of patients with genetically confirmed LQTS have a normal QTc.10,16

Molecular study may be aimed at a specific gene or may be guided by the ECG, syncope triggers or the characteristics of associated syndromes. In patients with congenital deafness, cardiac malformations, cognitive deficit, autism spectrum disorder and/or dysmorphisms, diagnostic hypotheses should include Jervell and Lange-Nielson, Timothy, or Andersen-Tawil syndromes. Alternatively the use of gene panels that screen multiple genes associated with LQTS can help diagnose rarer forms of the disease.17

Jervell and Lange-Nielson syndrome is an autosomal recessive disorder, more rarely compound heterozygous, involving the genes KCNQ1 or KCNE1, in which long QTc, usually >500 ms, is associated with congenital profound bilateral sensorineural hearing loss. It usually manifests as syncope following sympathetic activation.6,18 Timothy syndrome (LQTS type 8) is associated with pathogenic variants in CACNA1C and is characterized by atrioventricular conduction disturbances, tachyarrhythmias, congenital heart defects, hand/foot and facial dysmorphism, neurodevelopmental problems and autism spectrum disorder.6,19 Andersen-Tawil syndrome (LQTS type 7), associated with pathogenic variants of KCNJ2, besides prolonged QTc is characterized by the presence of U waves, hypokalemic periodic paralysis, facial dysmorphism and mild neurocognitive deficits, and regularly presents with palpitations, syncope, or periodic paralysis triggered by prolonged rest or rest following exertion.6,20

Genetic testing and genetic counseling are recommended in all individuals diagnosed as having or with a strong clinical suspicion of LQTS (class I),2,3 and may be considered in asymptomatic individuals with QTc >460 ms (prepuberty) or >480 ms (adults), in the absence of secondary causes (class IIb)2 (Table 1).

Short QT syndromeClinical diagnosis

SQTS is diagnosed in the presence of QTc ≤340 ms (class I), and should be considered (class IIa) in the presence of QTc ≤360 ms and one or more of the following: a confirmed pathogenic mutation; a family history of SQTS; a family history of SD at age <40 years; or survival from a VT/VF episode in the absence of structural heart disease.9

Genetic diagnosis

SQTS is associated with variants in three genes coding for potassium channels (KCNH2, KNCQ1 and KCNJ2), which are also associated with LQTS, although with the opposite effect in terms of functional alterations.6,10

Genetic testing may be considered in individuals with SQTC (class IIb)2,3 to facilitate screening of first-degree relatives.3 Unlike in LQTS, genetic testing has no prognostic value in SQTS.

Catecholaminergic polymorphic ventricular tachycardiaClinical diagnosis

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary arrhythmogenic syndrome that typically manifests with adrenergically mediated syncope or SD secondary to VT.21 Diagnosis is established by in the presence of a structurally normal heart, normal ECG and exercise- or emotion-induced bidirectional or polymorphic VT (class I) or in patients who are carriers of pathogenic mutation(s) in the genes RyR2 or CASQ2 (class I).9

Genetic diagnosis

Genetic testing is recommended in individuals with CPVT (class IIa3/class I2) (Table 1).

Cardiomyopathies

The cardiomyopathies are diseases in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease or congenital heart disease sufficient to cause the observed myocardial abnormality.22

Molecular study is nowadays an integral part of the assessment and management of patients with cardiomyopathies and their families, and is also used for diagnosis of familial forms.23,24

Hypertrophic cardiomyopathyClinical diagnosis

Hypertrophic cardiomyopathy (HCM) is defined by the presence of inappropriate left ventricular hypertrophy disproportionate to loading conditions or other cardiac or systemic factors sufficient to cause the observed anomaly. The diagnostic criterion is a maximum wall thickness of ≥15 mm in any left ventricular myocardial segment. In first-degree relatives, diagnosis is established by an otherwise unexplained wall thickness of ≥13 mm in any segment.25

Genetic diagnosis

Genetic testing (targeted or multiple gene panels) is recommended in patients with a clinical diagnosis of HCM (class I,2,25 class IIa,3,26 level A23), particularly when screening of family members is anticipated.25,26 Molecular diagnosis is also recommended when the clinical presentation suggests a particular genetic cause that is non-sarcomeric (class I).26

In patients fulfilling diagnostic criteria for HCM, genetic testing is positive in 30-60% of cases,25,27–29 higher in familial disease and lower in older patients and in those with non-standard clinical manifestations, including late onset, less severe hypertrophy, concentric hypertrophy or sigmoid septum, and absence of adverse events.25,28,29

Genetic testing in patients with a borderline diagnosis of HCM (left ventricular wall thickness 12-13 mm in adults; left ventricular hypertrophy in the presence of hypertension, athletic training, valve disease) should be performed only after detailed assessment by specialist teams (class IIa),25 since the result may also be equivocal: a negative result does not rule out the diagnosis and variants of uncertain significance are hard to interpret25 (Table 2).

Table 2.

Recommendations for genetic testing in cardiomyopathies.

Disease  Recommendation  R-LE  Source (year) 
HCMGenetic testing is recommended in patients fulfilling diagnostic criteria for HCM to confirm the diagnosis.  I-B  ESC (2014)25 
Comprehensive or targeted (MYBPC3, MYH7, TNNI3, TNNT2, TPM1) genetic testing is recommended for any patient with a clinical diagnosis of HCM based on clinical history, family history, and electrocardiographic/ echocardiographic findings.  I-C  HRS/EHRA (2011)2 
Genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause.  I-B  ACCF/AHA (2011)26 
Genetic testing is reasonable in individuals with confirmed or clinically suspected diagnosis of HCM to facilitate the identification of first-degree family members at risk for developing HCM.IIa-BHRS/EHRA (2011)2 
ACCF/AHA (2011)26 
Genetic testing in patients with a borderline diagnosis of HCM should be performed only after detailed assessment by specialist teams.  IIa-C  ESC (2014)25 
Genetic testing should be considered in the most clearly affected person in a family to facilitate family screening and management.  HFSA (2018)23 
DCMComprehensive or targeted (LMNA and SCN5A) genetic testing is recommended for patients diagnosed with DCM and significant cardiac conduction disease and/or a family history of premature unexpected SD.  I-C  HRS/EHRA (2011)2 
Genetic testing is recommended in the presence of a familial form of DCM or in sporadic DCM with clinical clues suggestive of a particular/rare genetic disease.  ESC (2016)24 
Genetic testing can be useful for patients with familial DCM to confirm the diagnosis, to recognize those who are at highest risk of arrhythmia and syndromic features.  IIa-C  HRS/EHRA (2011)2 
Genetic testing can be useful for patients with familial DCM to confirm the diagnosis, to facilitate cascade screening within the family, and to help with family planning.mod-A  AHA (2016)31 
IIa-C  HRS/EHRA (2011)2 
In patients with familial or idiopathic DCM, genetic testing can be useful in conjunction with genetic counseling.  mod-B  AHA (2016)31 
Genetic testing should be considered in the most clearly affected person in a family to facilitate family screening and management.  HFSA (2018)23 
ARVCComprehensive or targeted (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43):    HRS/EHRA (2011)2 
- can be useful for patients satisfying the diagnostic criteria for ARVC of the 2010 Task Force32  IIa-C   
- may be considered for patients with possible ARVC (1 major or 2 minor criteria of the 2010 Task Force32  IIb-C   
- is not recommended for patients with only a single minor criterion of the 2010 Task Force.32  III-C   
In patients with clinically diagnosed or suspected ARVC, genetic testing can be useful for diagnosis and for gene-specific targeted family screening.  IIa-B  AHA/ACC/HRS (2017)3 
Genetic testing should be considered in the most clearly affected person in a family to facilitate family screening and management.  HFSA (2018)23 
RCMGenetic testing may be considered for patients with a clinical index of suspicion of HCM based on clinical history, family history, and electrocardiographic/ echocardiographic findings.  IIb-C  HRS/EHRA (2011)2 
Genetic testing should be considered in the most clearly affected person in a family to facilitate family screening and management.  HFSA (2018)23 
LVNC  Genetic testing may be considered for patients with a clinical diagnosis of LVNC based on clinical history, family history, and electrocardiographic/echocardiographic findings.  IIa-C  HRS/EHRA (2011)2 

ACC: American College of Cardiology; AHA: American Heart Association; ARVC: arrhythmogenic right ventricular cardiomyopathy; DCM:dilated cardiomyopathy; EHRA: European Heart Rhythm Association; HCM: hypertrophic cardiomyopathy; HFSA: Heart Failure Society of America; HRS: Heart Rhythm Society; LE: level of evidence; LVNC: left ventricular non-compaction; mod: moderate level of evidence; R: class of recommendation; RCM: restrictive cardiomyopathy; SD: sudden death.

Phenocopies

Metabolic and other hereditary diseases account for a small, though important, proportion of patients with an HCM genotype. Conditions that more commonly cause HCM include Anderson-Fabry disease, Danon disease, amyloidosis and HCM caused by variants in the PRKAG2 gene. Differential diagnosis is crucial, since these diseases have very different natural history and prognosis, and may require different therapeutic approaches. Supplement 7 lists cardiac and extracardiac manifestations that can guide molecular diagnosis.

Dilated cardiomyopathyClinical diagnosis

Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause the observed degree of dysfunction. It is considered phenotypically related to hypokinetic non-dilated cardiomyopathy (HNDC), which is defined by the presence of left ventricular or biventricular systolic dysfunction (defined as left ventricular ejection fraction <45%) without dilatation.24

As molecular diagnostic techniques have improved, 25-50% of cases of DCM previously thought to be idiopathic have been found to have a genetic basis, mainly with autosomal dominant transmission.24,30,31 A comprehensive investigation of family history in index cases, covering at least three generations, is thus essential. In the absence of conclusive molecular genetic information in a family, DCM or HNDC is considered to be familial if two or more family members are affected or in the presence of an index patient fulfilling diagnostic criteria for DCM/HNDC and a first-degree relative with autopsy-proven DCM and SD by the age of 50 years.24

However, the lack of a family history does not exclude a genetic cause, and the latter should be considered especially when there are atrioventricular conduction disturbances, prior to or concomitant with ventricular dysfunction or skeletal myopathy.30 Other diagnostic criteria are used for familial forms (Table S4, Supplement 8).24

Genetic diagnosis

Genetic testing is recommended (class I) for patients diagnosed with DCM and significant cardiac conduction disease ((i.e., first-, second-, or third-degree heart block) and/or a family history of premature unexpected SD,2 and in patients with a familial form of DCM or in sporadic DCM with clinical clues suggestive of a particular/rare genetic disease.24 Genetic testing should be considered in the most clearly affected person in a family (level of evidence A)23 (Table 2).

Supplement 9 lists some manifestations of rare genetic forms of DCM that should prompt molecular diagnosis.

Genetic testing has a positive result in 30-40% of cases of DCM,31 higher in familial than in isolated cases (25-40% vs. 10-25%).23

Arrhythmogenic right ventricular cardiomyopathyClinical diagnosis

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is defined histologically by the progressive replacement of ventricular myocardium with adipose and fibrous tissue often confined to a ‘triangle of dysplasia’ comprising the right ventricular inflow, outflow, and apex.22 It is defined by the presence of right ventricular dysfunction (global or regional), with or without left ventricular disease, in the presence of histological evidence for the disease and/or abnormalities on ECG, echocardiography or cardiac magnetic resonance (CMR) (Table S5, Supplement 10).32

Although structural abnormalities predominate in the right ventricle, it is now known that involvement can be biventricular or even mainly in the left ventricle.33 There should be a high index of suspicion for this condition when non-ischemic late enhancement sparing the subendocardium is seen on CMR together with T-wave abnormalities on the ECG and ventricular arrhythmias, particularly in the presence of a family history of SD.34

Diagnosis in familial cases

When ARVC has been diagnosed in an index case, diagnosis in first-degree relatives requires only one of the following criteria: T-wave inversion in V1, V2 and V3 (over the age of 14 years); late potentials; VT with left bundle branch block morphology or >200 premature ventricular contractions in 24 hours; or mild right ventricular global or segmental dilatation or dysfunction.32

Genetic diagnosis

Comprehensive or targeted genetic testing can be useful for patients satisfying the diagnostic criteria for ARVC (class IIa2,3/level A23), and may be considered in possible cases (class IIb).2 The positivity rate for genetic testing in ARVC is usually around 50%35 (Table 2).

Restrictive cardiomyopathyClinical diagnosis

Restrictive cardiomyopathy (RCM) is rare and can be idiopathic, familial or secondary to systemic disorders. Characterized by a restrictive physiology, it is usually detected by echocardiography, which shows normal or reduced ventricular volumes and wall thicknesses that are not significantly increased (although wall thickness may be increased in infiltrative disease).22

Genetic diagnosis

Genetic testing may be considered for patients with HCM based on clinical history, family history, and electrocardiographic/echocardiographic findings (class IIb2/level B23) (Table 2).

Before genetic study is performed, differential diagnoses and specific diagnostic tests should be considered as listed in Supplement 11.

Left ventricular non-compactionClinical diagnosis

Left ventricular non-compaction (LVNC) is characterized by prominent left ventricular trabeculae and deep intertrabecular recesses with blood flow from the ventricular cavity and no communication with the coronary tree. Two layers of myocardium can be distinguished, compacted and non-compacted.22 In some individuals, LVNC is associated with ventricular dilatation and systolic dysfunction.22

It is not clear whether LVNC is a separate primary cardiomyopathy or merely a phenotypic trait shared by other cardiomyopathies and other pathological (neuromuscular and mitochondrial diseases and myopathies) and physiological conditions, including pregnancy and sports participation.23,36,37

There are various diagnostic criteria based on imaging studies (Table S6, Supplement 12).38–44

A diagnosis of cardiomyopathy is more likely when the quantitative short-axis echocardiographic criteria of Jenni38 or Jacquier43 are fulfilled together with one of the following factors: another affected family member (or family history of cardiomyopathy); ventricular dysfunction or wall motion abnormalities; symptoms or complications; neuromuscular disease; or one of several potentially causative genetic variants found in families with LVNC.45,46

Genetic diagnosis

Genetic testing may be considered for patients with a clinical diagnosis of LVNC based on clinical history, family history, and clinical (especially neuromuscular disease), electrocardiographic and echocardiographic findings (class IIa).2 It is not recommended in individuals with isolated LVNC or those without other abnormalities in ventricular structure or function, symptoms, or family history (Table 2).

Family screening in cardiomyopathies

Details of clinical and molecular assessment of relatives of patients with cardiomyopathies are given in Table S7, Supplement 13.

Hereditary aortopathies

Hereditary diseases of the aorta are a heterogeneous group of disorders characterized by aneurysms and/or dissection in one or more aortic segments, most often between the aortic annulus and the diaphragm. Depending on the presence or otherwise of manifestations in other organs, hereditary aortopathies can be classified as syndromic or non-syndromic. Associated genetic variants mainly affect extracellular matrix homeostasis, transforming growth factor-beta (TGF-β) signaling, and vascular smooth muscle cell contractility.47,48

In patients with thoracic aorta aneurysms or dissection, screening of first-degree relatives is recommended to identify possible familial forms (class I). Once a familial form is strongly suspected, it is recommended to refer the patient to a geneticist for family investigation and molecular testing (class I). In non-syndromic familial cases, screening for aneurysms should be considered throughout the arterial tree, including cerebral arteries (class IIa).49

The main syndromes associated with aortic aneurysms or dissection and indications for imaging of the aorta are listed in Tables S8.1, S8.2 and S8.3, Supplement 14.

Familial hypercholesterolemia

Although knowledge of familial hypercholesterolemia (FH) has improved in recent decades, this common genetic disease, which though potentially fatal is treatable, remains underdiagnosed and undertreated.50 Early diagnosis is essential to begin appropriate individualized treatment in order to prevent premature atherosclerotic disease, as well as to identify affected relatives and thus reduce the burden of cardiovascular disease in these families.

Clinical diagnosis

There are two main sets of diagnostic criteria for FH: those of the Simon Broome Register Group51 and those of the Dutch Lipid Clinic Network.52 The criteria most often used in Portugal are adapted from those of the Simon Broome Register, as follows:

Probable familial hypercholesterolemia

  • (a)

    Children under 16 years of age: >260 mg/dl or low-density lipoprotein (LDL) cholesterol >155 mg/dl; adults: total cholesterol >290 mg/dl or LDL cholesterol >190 mg/dl and

  • (b)

    family history of myocardial infarction before 50 years of age in grandparents or uncles/aunts or before 60 years of age in parents, siblings or children and/or

  • (c)

    family history of raised total cholesterol (>290 mg/dl in adults and >260 mg/dl in children under 16 years of age) in parents, siblings or children; or total cholesterol >290 mg/dl in grandparents or uncles/aunts.

Cholesterol levels should be measured on two different occasions, preferably 3-6 months after implementation of appropriate lifestyle changes.

Confirmed familial hypercholesterolemia

  • (a)

    The above criteria plus tendon xanthomas in first-degree (parents, siblings or children) or second-degree (grandparents or uncles/aunts) relatives or

  • (b)

    presence of a pathogenic or likely pathogenic variant in one of three genes associated with HF: LDLR, APOB, or PCSK9.

Genetic diagnosis

Genetic testing should be performed in individuals with definite or probable FH, as well as for their at-risk relatives, as recommended by the Journal of the American College of Cardiology expert panel.53

The test should include the genes LDLR, APOB and PCSK9, and whenever possible the genes associated with phenocopies of FH: LDLRAP1, APOE, LIPA, ABCG5 and ABCG8.53

Genetic testing provides prognostic information that can lead to more accurate risk stratification. Cascade screening of at-risk relatives is highly effective in identifying affected individuals who require appropriate treatment.

Individuals with confirmed FH, particularly those with homozygous FH, should be referred to a specialist in the condition. All FH patients should be offered a regular structured review that is carried out at least annually, since this can reduce cardiovascular morbidity and mortality through lifestyle interventions and prompt appropriate therapeutic measures.54

Congenital heart disease

Congenital heart disease (CHD) is the umbrella term for cardiovascular malformations present from birth, which are found in 1-1.2% of all live births.55 The actual prevalence is difficult to determine, since not all cases are diagnosed early, but it has been estimated at 13.1/1000 children and 6.1/1000 adults.56 Around 90% of cases are sporadic. Most children with CHD now survive to adulthood, although significant proportions require one or more surgical interventions or develop complications such as arrhythmias or heart failure.

The main etiological factors in CHD and methods of genetic diagnosis are listed in Supplement 15.

An increasing number of genetic variants associated with CHD have been identified in the last decade, including sporadic, hereditary, syndromic and non-syndromic forms. A definite genetic diagnosis may, for example, identify a non-cardiac phenotype, which will require specific management and treatment and will improve genetic counseling. Supplement 15 includes some common examples of syndromic CHD (Table S9.1) and data on the risk of recurrence in some CHD (Tables S9.2 and S9.3).

Pulmonary arterial hypertensionClinical diagnosis

Pulmonary arterial hypertension (PAH) is defined as mean pulmonary arterial pressure >20 mmHg associated with pulmonary artery wedge pressure ≤15 mmHg and pulmonary vascular resistance ≥3 Wood units at rest, measured by right heart catheterization.57

Around 70-80% of patients with PAH inherited in an autosomal dominant pattern58 and 10-20% with sporadic or idiopathic PAH59 have variants in the BMPR2 gene, which codes for a protein in the TGF-β family. Penetrance is greater in females in these variants.60

Other genes have been associated with PAH, including TBX4, ATP13A3, GDF2, SOX17, AQP1, ACVRL1, SMAD9, ENG, KCNK3 and CAV1.58 Variants in EIF2AK4 are associated with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis.61

Genetic diagnosis

Genetic testing and counseling should be offered to patients with hereditary or sporadic/idiopathic PAH. Genetic testing can identify asymptomatic carriers, but since penetrance is incomplete, it is currently impossible to predict who will develop the disease. Echocardiographic monitoring should be considered for such individuals.59,62 Identification of genetic variants in EIF2AK4 can avoid the need for pulmonary biopsy.58

Pre-implantation genetic diagnosis of PAH can enable selection of embryos for medically assisted reproduction.63

Sudden cardiac deathDefinitions

SD is defined as a non-traumatic, unexpected fatal event occurring within one hour of the onset of symptoms in an apparently healthy subject. If death is not witnessed, it is defined as death when the victim was in good health 24 hours before the event.9

Sudden arrhythmic death syndrome (SADS) is defined as SD when the cause of death is unknown or uncertain after autopsy, which is the case in 25-50% of young SD.64,65

SD in children aged under one year is known as sudden infant death syndrome. In this age-group, there is a complex relationship between various factors that can trigger SD, including a critical development period of the autonomic nervous system, exogenous stressors such as sleeping position, and the inherent vulnerability of the infant, including genetic factors.66

SD accounts for 15-25% of mortality in the general population and its incidence increases significantly with age.67–70 Over the age of 40 years, most cases are due to coronary artery disease,71 while hereditary cardiac conditions such as cardiomyopathies and channelopathies are more common in younger individuals.69

Primary electrical diseases such as LQTS, BrS and CPVT are not easy to identify postmortem, and postmortem genetic testing (molecular autopsy) is particularly useful in these cases. In SADS, genetic testing can identify the cause of death in an additional 20-30% of cases. It should be noted that genetic variants associated with channelopathies, especially LQTS and CPVT, have been identified in around 20% of patients previously diagnosed with epilepsy.72

Autopsy and postmortem genetic testing

In cases of SD, it is important to diagnose hereditary heart disease so that at-risk living relatives (asymptomatic carriers) can be identified, in order to intervene early and to modify the course of their lives.70

An autopsy is recommended to investigate the causes of SD (class I).9 The guidelines for autopsies in these cases were recently updated by the Association for European Cardiovascular Pathology.73 Ideally, information should be collected on the personal and family medical history of the deceased and the circumstances of death. The cardiac examination should be performed by an experienced pathologist and biological material should be obtained for genetic study, if performed. Handling of this material requires the consent of the deceased’s family.74

The results of the autopsy should be communicated to the family. Referral networks should be in place for appropriate clinical assessment of relatives. Postmortem genetic testing should only be performed after relatives receive genetic counseling75 and is indicated when hereditary heart disease is suspected, whether suggested by autopsy results or in cases of SADS (class IIa).9

In the context of SADS, genetic study should include genes associated with channelopathies and cardiomyopathies. Although the latter cause structural changes in the myocardium, these may be subtle and undetected on autopsy.76

As by definition there is no identified phenotype in cases of SD, even if a genetic variant is identified its pathogenicity often cannot be established. It is thus important to integrate this information with the results of familial screening.72

Screening of relatives

According to the European Society of Cardiology guidelines, whether or not molecular autopsy is performed, screening of first-degree relatives of SD victims is recommended (class I).9 Screening should initially include clinical assessment, ECG, stress testing and echocardiography and then, depending on the level of clinical suspicion, CMR, 24-h Holter, and provocative testing with ajmaline/flecainide.9

In the absence of a definitive diagnosis, following a thorough assessment (which may include genetic study), first-degree relatives should be monitored periodically until adulthood, by which time most relevant diseases will have reached phenotypic expression.9 When the results of autopsy and molecular study are negative, the event rate in relatives of SD victims appears to be low.77

Conflicts of interest

The authors have no conflicts of interest to declare.

Appendix A
Supplementary data

The following are Supplementary data to this article:

References
[1]
S. Richards, N. Aziz, S. Bale, et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Genet Med., 17 (2015), pp. 405-424
[2]
M.J. Ackerman, S.G. Priori, S. Willems, 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).
Europace., 13 (2011), pp. 1077-1109
[3]
S.M. Al-Khatib, W.G. Stevenson, M.J. Ackerman, et al.
2017 AHA/ACC/HRS guideline 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 on Clinical Practice Guidelines and the Heart Rhythm Society.
Heart Rhythm., 15 (2018), pp. e73-e189
[4]
B.J. Maron, J.A. Towbin, G. Thiene, et al.
Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
Circulation., 113 (2006), pp. 1807-1816
[5]
J. Sieira, P. Brugada.
The definition of the Brugada syndrome.
Eur Heart J., 38 (2017), pp. 3029-3034
[6]
M. Cerrone, S.G. Priori.
Genetics of sudden death: focus on inherited channelopathies.
Eur Heart J., 32 (2011), pp. 2109-2118
[7]
C. Antzelevitch, G.X. Yan.
J wave syndromes.
Heart Rhythm., 7 (2010), pp. 549-558
[8]
C. Antzelevitch, G.X. Yan, M.J. Ackerman, et al.
J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge.
Europace, 19 (2017), pp. 665-694
[9]
S.G. Priori, C. Blomstrom-Lundqvist, A. Mazzanti, et al.
2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
Eur Heart J., 36 (2015), pp. 2793-2867
[10]
S.G. Priori, A.A. Wilde, M. Horie, et al.
HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013.
Heart Rhythm., 10 (2013), pp. 1932-1963
[11]
P.W. Macfarlane, C. Antzelevitch, M. Haissaguerre, et al.
The early repolarization pattern: a consensus paper.
J Am Coll Cardiol., 66 (2015), pp. 470-477
[12]
P.J. Schwartz, L. Crotti.
QTc behavior during exercise and genetic testing for the long-QT syndrome.
Circulation., 124 (2011), pp. 2181-2184
[13]
J.R. Giudicessi, M.J. Ackerman.
Genotype- and phenotype-guided management of congenital long QT syndrome.
Curr Probl Cardiol., 38 (2013), pp. 417-455
[14]
S.G. Priori, P.J. Schwartz, C. Napolitano, et al.
Risk stratification in the long-QT syndrome.
N Engl J Med., 348 (2003), pp. 1866-1874
[15]
P.J. Schwartz, M.J. Ackerman, A.L. George, et al.
Impact of genetics on the clinical management of channelopathies.
J Am Coll Cardiol., 62 (2013), pp. 169-180
[16]
I. Goldenberg, S. Horr, A.J. Moss, et al.
Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals.
J Am Coll Cardiol., 57 (2011), pp. 51-59
[17]
M. Alders, H. Bikker, I. Christiaans.
Long QT Syndrome.
GeneReviews®, pp. 1993-2019
[18]
L. Tranebjaerg, R.A. Samson, G.E. Green.
Jervell and Lange-Nielson Syndrome.
[19]
C. Napolitano, I. Splawski, K.W. Timothy, et al.
Timothy Syndrome.
[20]
A. Veerapandiyan, J.M. Statland, R. Tawil.
Andersen-Tawil Syndrome.
[21]
S.G. Priori, C. Napolitano, M. Memmi, et al.
Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.
[22]
P. Elliott, B. Andersson, E. Arbustini, et al.
Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases.
Eur Heart J., 29 (2008), pp. 270-276
[23]
R.E. Hershberger, M.M. Givertz, C.Y. Ho, et al.
Genetic evaluation of cardiomyopathy-a heart failure society of America Practice Guideline.
J Card Fail., 24 (2018), pp. 281-302
[24]
Y.M. Pinto, P.M. Elliott, E. Arbustini, et al.
Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases.
Eur Heart J., 37 (2016), pp. 1850-1858
[25]
Authors/Task Force members, P.M. Elliott, A. Anastasakis, M.A. Borger, et al.
2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
Eur Heart J., 35 (2014), pp. 2733-2779
[26]
B.J. Gersh, B.J. Maron, R.O. Bonow, et al.
2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
J Am Coll Cardiol., 58 (2011), pp. e212-60
[27]
B.J. Maron, M.S. Maron, B.J.A. Maron, et al.
Moving beyond the sarcomere to explain heterogeneity in hypertrophic cardiomyopathy: JACC review topic of the week.
J Am Coll Cardiol., 73 (2019), pp. 1978-1986
[28]
C. Ko, P. Arscott, M. Concannon, et al.
Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup.
Genet Med., 20 (2018), pp. 69-75
[29]
M.A. Burke, S.A. Cook, J.G. Seidman, et al.
Clinical and mechanistic insights into the genetics of cardiomyopathy.
J Am Coll Cardiol., 68 (2016), pp. 2871-2886
[30]
L. Mestroni, B. Maisch, W.J. McKenna, et al.
Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy.
Eur Heart J., 20 (1999), pp. 93-102
[31]
B. Bozkurt, M. Colvin, J. Cook, et al.
Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
Circulation., 134 (2016), pp. e579-e646
[32]
F.I. Marcus, W.J. McKenna, D. Sherrill, et al.
Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria.
Eur Heart J., 31 (2010), pp. 806-814
[33]
D. Corrado, M.S. Link, H. Calkins.
Arrhythmogenic Right Ventricular Cardiomyopathy.
N Engl J Med., 376 (2017), pp. 61-72
[34]
C. Basso, K. Pilichou, B. Bauce, et al.
Diagnostic criteria, genetics, and molecular basis of arrhythmogenic cardiomyopathy.
Heart Fail Clin., 14 (2018), pp. 201-213
[35]
A. Bhonsale, J.A. Groeneweg, C.A. James, et al.
Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers.
Eur Heart J., 36 (2015), pp. 847-855
[36]
E. Arbustini, F. Weidemann, J.L. Hall.
Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?.
J Am Coll Cardiol., 64 (2014), pp. 1840-1850
[37]
E. Oechslin, R. Jenni.
Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity?.
Eur Heart J., 32 (2011), pp. 1446-1456
[38]
R. Jenni, E. Oechslin, J. Schneider, et al.
Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy.
Heart., 86 (2001), pp. 666-671
[39]
T.K. Chin, J.K. Perloff, R.G. Williams, et al.
Isolated noncompaction of left ventricular myocardium. A study of eight cases.
Circulation., 82 (1990), pp. 507-513
[40]
C. Stollberger, J. Finsterer, G. Blazek.
Left ventricular hypertrabeculation/noncompaction and association with additional cardiac abnormalities and neuromuscular disorders.
Am J Cardiol., 90 (2002), pp. 899-902
[41]
C. Stollberger, B. Gerecke, J. Finsterer, et al.
Refinement of echocardiographic criteria for left ventricular noncompaction.
Int J Cardiol., 165 (2013), pp. 463-467
[42]
S.E. Petersen, J.B. Selvanayagam, F. Wiesmann, et al.
Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging.
J Am Coll Cardiol., 46 (2005), pp. 101-105
[43]
A. Jacquier, F. Thuny, B. Jop, et al.
Measurement of trabeculated left ventricular mass using cardiac magnetic resonance imaging in the diagnosis of left ventricular non-compaction.
Eur Heart J., 31 (2010), pp. 1098-1104
[44]
C. Gebhard, B.E. Stahli, M. Greutmann, et al.
Reduced left ventricular compacta thickness: a novel echocardiographic criterion for non-compaction cardiomyopathy.
J Am Soc Echocardiogr., 25 (2012), pp. 1050-1057
[45]
G. Captur, V. Muthurangu, C. Cook, et al.
Quantification of left ventricular trabeculae using fractal analysis.
J Cardiovasc Magn Reson., 15 (2013), pp. 36
[46]
P. Garcia-Pavia, J.L. de la Pompa.
Left ventricular noncompaction: a genetic cardiomyopathy looking for diagnostic criteria.
J Am Coll Cardiol., 64 (2014), pp. 1981-1983
[47]
A. Verstraeten, I. Luyckx, B. Loeys.
Aetiology and management of hereditary aortopathy.
Nat Rev Cardiol., 14 (2017), pp. 197-208
[48]
B.J.M. Mulder, I.M.B.H. van de Laar, J. de Backer.
Heritable Thoracic Aortic Disorders.
Clinical Cardiogenetics, 2nd ed., pp. P263-94
[49]
R. Erbel, V. Aboyans, C. Boileau, et al.
2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).
Eur Heart J., 35 (2014), pp. 2873-2926
[50]
B.G. Nordestgaard, M.J. Chapman, S.E. Humphries, et al.
Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
Eur Heart J., 34 (2013), pp. 3478-3490a
[51]
Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.
BMJ., 303 (1991), pp. 893-896
[52]
J.C. Defesche, P.J. Lansberg, M.A. Umans-Eckenhausen, et al.
Advanced method for the identification of patients with inherited hypercholesterolemia.
Semin Vasc Med., 4 (2004), pp. 59-65
[53]
A.C. Sturm, J.W. Knowles, S.S. Gidding, et al.
Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel.
J Am Coll Cardiol., 72 (2018), pp. 662-680
[54]
NICE NCC for PC.
Identification and Management of Familial Hypercholesterolaemia. NICE Clinical Guideline 71.
National Institute for Health and Clinical Excellence, (2008), pp. P45
[55]
D. van der Linde, E.E. Konings, M.A. Slager, et al.
Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis.
J Am Coll Cardiol., 58 (2011), pp. 2241-2247
[56]
A.J. Marelli, R. Ionescu-Ittu, A.S. Mackie, et al.
Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010.
Circulation., 130 (2014), pp. 749-756
[57]
G. Simonneau, D. Montani, D.S. Celermajer, et al.
Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
[58]
N.W. Morrell, M.A. Aldred, W.K. Chung, et al.
Genetics and genomics of pulmonary arterial hypertension.
[59]
F. Soubrier, W.K. Chung, R. Machado, et al.
Genetics and genomics of pulmonary arterial hypertension.
J Am Coll Cardiol., 62 (2013), pp. D13-21
[60]
E.K. Larkin, J.H. Newman, E.D. Austin, et al.
Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension.
Am J Respir Crit Care Med., 186 (2012), pp. 892-896
[61]
M. Eyries, D. Montani, B. Girerd, et al.
EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension.
Nat Genet., 46 (2014), pp. 65-69
[62]
N. Galiè, G. Simonneau.
The Fifth World Symposium on pulmonary hypertension.
J Am Coll Cardiol., 62 (2013), pp. D1-3
[63]
N. Frydman, J. Steffann, B. Girerd, et al.
Pre-implantation genetic diagnosis in pulmonary arterial hypertension due to BMPR2 mutation.
Eur Respir J., 39 (2012), pp. 1534-1535
[64]
A. Vos, A.C. van der Wal, A.H. Teeuw, et al.
Cardiovascular causes of sudden unexpected death in children and adolescents (0-17 years): a nationwide autopsy study in the Netherlands.
Neth Heart J., 26 (2018), pp. 500-505
[65]
C. Semsarian, J. Ingles, A.A. Wilde.
Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives.
Eur Heart J., 36 (2015), pp. 1290-1296
[66]
D.J. Tester, L.C.H. Wong, P. Chanana, et al.
Cardiac genetic predisposition in sudden infant death syndrome.
J Am Coll Cardiol., 71 (2018), pp. 1217-1227
[67]
J.J. de Vreede-Swagemakers, A.P. Gorgels, W.I. Dubois-Arbouw, et al.
Out-of-hospital cardiac arrest in the 1990’s: a population-based study in the Maastricht area on incidence, characteristics and survival.
J Am Coll Cardiol., 30 (1997), pp. 1500-1505
[68]
M. Hayashi, W. Shimizu, C.M. Albert.
The spectrum of epidemiology underlying sudden cardiac death.
Circ Res., 116 (2015), pp. 1887-1906
[69]
C.X. Wong, A. Brown, D.H. Lau, et al.
Epidemiology of sudden cardiac death: global and regional perspectives.
Heart Lung Circ., 28 (2019), pp. 6-14
[70]
S. Ribeiro, L. Coelho, K. Puentes, et al.
Post mortem genetic test, the clinical diagnosis is not fade with the death of the patient.
Rev Port Cardiol., 38 (2019), pp. 503-509
[71]
D.P. Zipes, H.J. Wellens.
Sudden cardiac death.
Circulation., 98 (1998), pp. 2334-2351
[72]
N. Lahrouchi, H. Raju, E.M. Lodder, et al.
Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome.
J Am Coll Cardiol., 69 (2017), pp. 2134-2145
[73]
C. Basso, B. Aguilera, J. Banner, et al.
Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology.
Virchows Arch., 471 (2017), pp. 691-705
[74]
K. Michaud, F. Fellmann, H. Abriel, et al.
Molecular autopsy in sudden cardiac death and its implication for families: discussion of the practical, legal and ethical aspects of the multidisciplinary collaboration.
Swiss Med Wkly., 139 (2009), pp. 712-718
[75]
C. Semsarian, J. Ingles.
Molecular autopsy in victims of inherited arrhythmias.
J Arrhythm., 32 (2016), pp. 359-365
[76]
G. Sarquella-Brugada, O. Campuzano, S. Cesar, et al.
Sudden infant death syndrome caused by cardiac arrhythmias: only a matter of genes encoding ion channels?.
Int J Legal Med., 130 (2016), pp. 415-420
[77]
C. van der Werf, L. Stiekema, H.L. Tan, et al.
Low rate of cardiac events in first-degree relatives of diagnosis-negative young sudden unexplained death syndrome victims during follow-up.
Heart Rhythm., 11 (2014), pp. 1728-1732
[78]
C. Rapezzi, E. Arbustini, A.L. Caforio, et al.
Diagnostic work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases.
Eur Heart J., 34 (2013), pp. 1448-1458
[79]
P. Charron, M. Arad, E. Arbustini, et al.
Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.
Eur Heart J., 31 (2010), pp. 2715-2726
[80]
B.L. Loeys, H.C. Dietz, A.C. Braverman, et al.
The revised Ghent nosology for the Marfan syndrome.
J Med Genet., 47 (2010), pp. 476-485
[81]
H. Baumgartner, P. Bonhoeffer, N.M. De Groot, et al.
ESC Guidelines for the management of grown-up congenital heart disease (new version 2010).
Eur Heart J., 31 (2010), pp. 2915-2957
[82]
C.A. Warnes, R.G. Williams, T.M. Bashore, et al.
ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease). Developed in Collaboration With the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
J Am Coll Cardiol., 52 (2008), pp. e143-e263
[83]
K.K. Stout, C.J. Daniels, J.A. Aboulhosn, et al.
2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
[84]
J. Goodship, C. Wren.
Congenital cardiovascular malformations.
Principles and Practice of Clinical Cardiovascular Genetics, 7ª ed., pp. P130-50
[85]
M.E. Pierpont, M. Brueckner, W.K. Chung, et al.
Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association.
Circulation., 138 (2018), pp. e653-e711
[86]
A.E. Roberts, J.E. Allanson, M. Tartaglia, et al.
Noonan syndrome.
Lancet., 381 (2013), pp. 333-342
[87]
R.B. Hinton Jr, L.J. Martin, M.E. Tabangin, et al.
Hypoplastic left heart syndrome is heritable.
J Am Coll Cardiol., 50 (2007), pp. 1590-1595
[88]
J.R. Cowan, S.M. Ware.
Genetics and genetic testing in congenital heart disease.
Clin Perinatol., 42 (2015), pp. 373-393
[89]
J.J. Nora, K. Berg, A.H. Nora.
Congenital Heart Disease: Genetics. In: Cardiovascular Diseases: Genetics, Epidemiology and Prevention.
6ª ed., Oxford University Press, (1991), pp. P53-80

Please cite this article as: Sousa A, Moldovan O, Lebreiro A, Bourbon M, António N, Rato Q, et al. Recomendações para a realização de testes genéticos em cardiologia – revisão das principais diretrizes internacionais. Rev Port Cardiol. 2020;39:597–610.

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