CHAPTER 9: GENETIC BASIS OF CARDIOVASCULAR DISEASE

Individual living organisms are unique because their genes harbor a unique code of DNA. Human genetics explores variation, evolution, and deviation from “normal” genetic structure and function. Medical genetics is the study of genetic diseases caused by changes that can involve entire chromosomes or much smaller regions, even single nucleotides. Its application in medicine encompasses all disciplines, as genetic diseases may affect multiple organs, often in the same individual.

Genetic cardiovascular diseases include chromosomal disorders (ie, congenital heart defects, congenital heart disease [CHD]), single-gene or monogenic diseases (ie, cardiomyopathies [CMPs], heritable aortic diseases), and multigenic/multifactorial disorders (ie, ischemic heart disease [IHD], atherosclerosis, diabetes). They may occur in the context of syndromes or exclusively involve the heart (ie, CMPs) or vessels (ie, heritable aortopathies). The burden of monogenetic cardiovascular diseases is difficult to establish. Some cardiac genetic diseases are common (ie, hypertrophic cardiomyopathy [HCM], some CHD), whereas others are extremely rare (pure restrictive cardiomyopathy [RCM], arterial tortuosity syndrome); however, most of them demonstrate clinical and genetic heterogeneity. This chapter provides a short summary of the classification of genetic diseases¹ and the clinical and molecular genetic workup in cardiovascular diseases. It revises the clinical and molecular genetics of major and emerging groups of genetic cardiovascular diseases, highlighting disease-specific genetic needs.

Chromosomal Disorders

Chromosomal disorders occur when there is a gain or loss of chromosomes, or parts of them. Several chromosomal abnormalities are associated with cardiovascular diseases, both syndromes with cardiovascular involvement and heart defects as unique phenotypes. The three major categories of chromosomal disorders are:

1. Those that involve the number of autosomes,² typically trisomy 21 (or Down syndrome) that commonly shows atrioventricular septal defects

2. Those that are caused by structural abnormalities of autosomes, typically translocations of large segments of chromosomes, as well as smaller insertions, deletions, or rearrangements, such as in 22q11 deletion syndromes that are associated with different CHDs³

3. Those that involve the sex chromosomes, typically Turner syndrome in females that in the classic form carries a unique X chromosome (45,X).⁴ In addition to the typical traits of the syndrome (short stature, webbed neck, and incomplete or absent development of secondary sex characteristics, leading to infertility), this syndrome often manifests with bicuspid aortic valve, aortic coarctation and aortic aneurysm.

Single-Gene Diseases: Mendelian Inheritance

Single-gene diseases are caused by mutations affecting a specific gene. The vast majority of genetic cardiovascular diseases are inherited according to Mendelian rules.¹ Based on inheritance pattern, they can be divided into autosomal dominant (AD), autosomal recessive (AR), or X-linked (XL) diseases (Fig. 9–1).

AD diseases can be transmitted by either parent and clinically manifest in heterozygous patients, who receive a mutated allele from one parent and a normal allele from the other. The graphic view of families in pedigrees typically shows that the disease passes from one generation to the next (vertical transmission). The majority of genetic cardiovascular diseases are AD, such as:

• Familial CMPs (up to 90% of cases)⁵

• Marfan syndrome (MFS) caused by mutations in the FBN1 gene, and other heritable aortic aneurysmal diseases⁶

• AD familial hypercholesterolemia⁷

• Carney syndrome with atrial myxoma⁸

• Primary pulmonary hypertension caused by defects of the BMPR2 gene⁹

• Atrial fibrillation caused by mutations in the NPPA gene¹⁰

In AR diseases, the effect of the mutated allele only manifests in homozygous (or compound heterozygous) mutation carriers. The pedigrees may show affected siblings with healthy parents (horizontal transmission). Known AR cardiovascular diseases are far less common than AD diseases, but they include rare CMPs, such as atrial dilated cardiomyopathy (ADCM) caused by homozygous mutations in the NPPA gene,¹¹ sick sinus syndrome caused by mutations in the SCN5A gene,^12,13 and aneurysmal diseases such as arterial tortuosity syndrome (ATS).¹⁴ In addition, several lysosomal storage diseases involving the heart and vessels are AR diseases.¹⁵ Increased risk of AR diseases occurs in the setting of consanguinity or in the context of geographically isolate populations.

In XL diseases, the mutated gene is located on the X chromosome. Because most XL diseases demonstrate recessive (XLR) inheritance, heterozygous females are phenotypically healthy. XLR diseases are characterized by absence of male-to-male transmission, obligate carrier status in daughters of affected males, and 50% probability that healthy heterozygous female carriers will pass the mutated gene to each child. In addition, male children who inherit the mutated gene will be hemizygotes and affected, and daughters who receive the mutated gene will be healthy carriers. Examples of XLR cardiovascular diseases include dilated cardiomyopathies (DCMs) caused by defects of dystrophin or emerin.^16,17 Female carriers may occasionally show mild and late-onset phenotypes as a result of nonrandom X inactivation (ie, mothers or sisters of patients with dystrophin defects may show increased serum creatine phosphokinase [CPK] levels or late-onset, slowly progressing DCM). XL dominant diseases are extremely rare, and very few examples of cardiovascular genetic diseases may show this pattern (ie, rare aneurysmal diseases caused by mutations in filamin A [MIM# 300049¹⁸] and rare CMPs¹⁹).

Non-Mendelian Inheritance: Diseases Caused by Mitochondrial DNA Mutations

Human mitochondria contain several molecules of circular polycistronic mitochondrial DNA (mtDNA). Mitochondria are present in oocytes and nearly absent in spermatozoa; thus, only mothers can pass on diseases associated with defects in mitochondrial genes (maternal or matrilineal inheritance) (see Fig. 9–1F).²⁰ Therefore, affected mothers will pass on the mutation to all daughters and sons, and affected fathers cannot pass on the mtDNA mutation. The disease clinically manifests when the amount of mutated mtDNA is higher than threshold levels. Typical cardiovascular phenotypes include hypertrophic (symmetric), nonobstructive CMPs that evolve through end-stage dilation and dysfunction similar to DCM; a “family marker” of mtDNA-related diseases is the phenotype heterogeneity in family members who carry the mutation.^19,21,22 Depending on the amount of mutated DNA, some family members may have CMP; others may manifest with different combinations of encephalomyopathy, hearing loss, ocular defects, diabetes or renal failure (Fig. 9–2).

Non-Mendelian Inheritance: Anticipation and Triplet Expansion

Triplet expansions within or near specific genes may show a distinct pattern of non-Mendelian inheritance termed anticipation.¹ Specifically, the age of onset decreases and the severity increases with the increase of instability (number of triplet repeats). When a “full expansion” mutation is achieved, the inheritance follows Mendelian rules. There are no known genetic “isolated” cardiovascular diseases demonstrating clinical anticipation through triplet expansion mechanisms.

Triplet expansion is well recognized in diseases such as Steinert muscle dystrophy²³ or Friedreich’s ataxia that typically involve heart.²⁴ Steinert muscle dystrophy²³ is caused by mutant CTG expansion in the nontranslating region of the dystrophia myotonica protein kinase gene and typically shows conduction disease and possible DCM. In Friedreich’s ataxia caused by GAA trinucleotide repeat expansion in intron 1 of the Frataxin gene, the heart shows early HCM that evolves through replacement fibrosis leading to recession of hypertrophy, reduction of global myocardial function, and electrical instability.²⁴ Friedreich’s hearts also show myocarditis and intramyocyte iron storage; the former finding should be differentiated from infectious myocarditis.²⁵ Both are examples of diseases in which cardiac involvement can be the major determinant of clinical outcome.

Diseases Associated with Imprinted Gene Mutations

Imprinting involves a sex-specific modification of imprinted genes, resulting in nonequal expression and depending on the sex of the parent of origin.¹ Maternally imprinted genes are expressed when inherited from the father (Prader-Willi syndrome), and paternally imprinted genes are expressed when inherited from the mother (Angelman syndrome). Although there are no examples of imprinted genetic cardiovascular diseases, imprinted genes (ie, ZAC, zinc finger protein associated with apoptosis and cell cycle arrest, and HYMAI, imprinted in hydatidiform mole) have been identified as potential candidates in rare forms of diabetes (ie, transient neonatal diabetes). In addition, patients with Prader-Willi syndrome may show CHD,²⁶ develop DCM,²⁷ demonstrate increased cardiac mass when treated with growth hormone,²⁸ require heart rate monitoring during functional analysis evaluating self-injurious behaviors,²⁹ or deserve cardiac evaluation, including two-dimensional (2D) speckle tracking echocardiography to evaluate the frequent systolic dysfunction in children.³⁰

Multifactorial Inheritance

Multifactorial diseases are the most common human diseases: the contribution of small effects of multiple genes adds to the effects of exogenous, environmental factors, which result in disease manifestation.¹ Common multifactorial diseases include IHD, hypertension, and diabetes.^31,32,33 Large genome-wide association studies (GWAS) have identified many gene loci, each of them potentially contributing to multiple disease states, including coronary atherosclerosis, IHD, classical risk factors, thrombosis, inflammation in coronary artery disease (CAD), and angioneogenesis. The risk of disease and recurrence is far from predictable, but is much lower than in monogenic diseases and proportional to the number of affected relatives, closeness of familial relationship and, in the case of myocardial infarction (MI), when the affected relative is of the less commonly affected gender (female). Typically, sons of mothers who develop premature MI are at higher risk than sons of fathers who experience premature MI.

Clinical Genetics

Clinical genetic workup includes comprehensive phenotype evaluation/deep phenotyping in probands, genetic counseling, pedigree generation, and clinical family screening. When present, certain phenotypic traits, including learning disabilities, facilitate family studies and genetic evaluation. However, most genetic cardiovascular diseases only affect the heart or large vessels and, unless they cause symptoms, their presence can be undetected. Typical examples of such include CMPs,³⁴ familial aneurysmal diseases,³⁵ small myxomas in Carney complex,³⁶ early pulmonary hypertension, or asymptomatic CHD.

In probands, physical examination includes evaluation of anthropometric features, skin, eyes, hair, musculoskeletal traits, and central nervous system abnormalities, among others.³⁷ Cardiologic assessment includes electrocardiography (ECG) and 2D echocardiography. A 24-hour Holter monitor may add information about nonperceived arrhythmias. Cardiac magnetic resonance or computed tomography (CT) can further contribute to phenotype characterization.³⁸ For syndromic genetic diseases involving the cardiovascular system, family screening is facilitated by common traits that may be seen in particular diseases, such as craniofacial, musculoskeletal, and ocular traits in patients with MFS, Loeys-Dietz syndrome (LDS), or Ehlers-Danlos syndrome (EDSIV); myopathy or learning disabilities in Danon syndrome; muscle involvement in Duchenne, Becker, or Emery Dreifuss muscular dystrophy; and pigmented lesions of the skin or tumors in Carney complex³⁶ or LEOPARD syndrome.³⁹

Clinical family screening is an extremely important tool for diagnosing familial disease. Current knowledge of heritable CMPs or nonsyndromic aortopathies strongly supports the strategy of investigating relatives regardless of genetic testing.³⁸ Baseline screening is noninvasive and includes physical examination, ECG and 2D echocardiography; further investigation can be performed if needed. Depending on the disease, relatives may have abnormalities in ECG and/or echocardiographic indices that predict the manifestation of the full phenotype. The collection of phenotype data in family members may contribute to the clinical diagnosis. Specifically, some traits of the disease can be present in early phases of the disease and lost in advanced phases; a representative example is the early short PR interval in the heart in Anderson Fabry disease (AFD) versus the late atrioventricular block in advanced Fabry CMPs.⁴⁰ Phenotype heterogeneity in affected family members can by itself be a marker of disease, with hearing loss, diabetes, renal failure, HCM, cryptogenic stroke, and ocular problems, differently manifested in the different family members with mtDNA-related diseases such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).⁴¹

Genetic Testing

Depending on the disease, chromosomal analysis or sequencing-based genetic testing is performed in probands first and subsequently in relatives.

Chromosomal analysis is done in cells able to divide in culture: amniocytes, fibroblasts from skin biopsies, stimulated T cells, and bone marrow cells. A conventional prenatal test (amniocentesis or villocentesis) is going to be replaced in the near future by noninvasive prenatal testing (NIPT) using cell-free fetal DNA. Although NIPT currently has very high sensitivity and specificity for diseases such as Down syndrome and slightly lower sensitivity for Edwards and Patau syndromes, it is not 100% accurate and should not be used as a final diagnosis for positive cases.⁴²

Gene analysis (test) is usually done using DNA isolated from blood samples. DNA can now be easily obtained from saliva, especially in children. In the past, each candidate gene was analyzed using Sanger-based automated sequencing, which was costly and time consuming. Today, genetic tests are routinely performed using next-generation sequencing (NGS) of multiple genes; Sanger sequencing is used for confirmation of the mutation identified by NGS and for cascade genetic testing in relatives.⁴³ Prenatal diagnosis can be performed on a regular basis, in particular for malignant diseases that are fully predicted by genetic testing. Noninvasive prenatal diagnosis for diseases such as dystrophinopathies seems to be accurate and reliable but requires further validation.⁴⁴

Genetic testing identifies gene variants/mutations. Pathogenic mutations are single-base substitutions in coding, splicing-relevant and regulatory regions of disease genes, or microrearrangements such as microdeletions, microinsertions, combined microinsertions and microdeletions (“indels”), and macrodeletions. Single-base mutations can be characterized as missense (the majority) or nonsense, or they may affect canonic splice sites. In human genetic diseases, single-base substitutions are far more common than other types of gene defects. However, prevalence of the types of gene defects varies in different disease genes: that is, up to 80% of genetic defects causing dystrophin-related diseases are large deletions. The interpretation of the pathogenicity of gene defects is a multistep process that starts with identification of the defects and progresses with possible functional or pathologic studies and family segregation studies. A pipeline for interpretation of genetic variants is summarized in Fig. 9–3.⁴⁵ In genes such as MYBPC3 or BMPR2, mutations predicting premature truncation of the protein are common, whereas up to 90% of mutations in MYH7 associated with HCM are single nucleotide missense mutations. Caution should be advised in assigning a pathogenic role to frameshift mutations just because they predict a truncated protein. Frameshift variants such as p.Ala897LysfsX4 in DSC2 (http://www.arvcdatabase.info/) clearly demonstrate that not all frameshift mutations are pathogenic. A recent systematic analysis of titin (TTN) truncating variants in publicly available reference populations, including the Exome Aggregation Consortium, found that 1 in 500 individuals carries a truncation in TTN A-band; this suggests that the penetrance of these potentially harmful variants is still poorly understood and that some of these variants do not necessarily manifest as AD DCM.⁴⁶

Interpretation of the results of genetic testing is based on (1) family segregation studies (affected members are mutation carriers and nonaffected members do not carry the putative mutations),⁴⁷ (2) pathologic analysis in samples of affected tissues, (3) effects of the mutation on protein expression in vivo (ie, cardiolaminopathies, cardiodystrophynopathies, Danon disease, AFD) or in in vitro systems (Fig. 9–4).

Cardiomyopathies: Still Paradigm of Idiopathic Diseases?

Definition

CMPs are myocardial disorders characterized by structurally and functionally abnormal heart muscle and absence of other diseases sufficient to cause the observed myocardial abnormality.⁴⁸ The morphofunctional phenotypes DCM, HCM, RCM, arrhythmogenic right, left and biventricular cardiomyopathy (ARC), and left ventricular noncompaction cardiomyopathy (LVNC) drive the currently used clinical classifications. In this context, LVNC is still a debated entity that is considered a genetic CMP in the American Heart Association, or AHA, classification⁴⁹ and a nonclassified entity in the European Society of Cardiology (ESC) classification.⁴⁸ More recently, the novel MOGE(S) nosology endorsed by the WHF proposed a simple description of the trait in individuals with either normal left ventricular size and wall thickness and preserved systolic and diastolic function, or in combination with HCM, RCM or DCM or ARVC^19,34 (for classification of CMPs, see Chap. 57). Each subtype of CMP is described in detail in Chaps. 58, 59 60. Here, we aim to highlight concepts and workup shared by all CMPs.

CMPs have been considered for decades as being the paradigm of “idiopathic myocardial diseases.” This concept will be progressively abandoned as their causes are identified. Most of them in fact have a precise and detectable genetic cause. CMPs now represent one of the fields of development of precision cardiology, with progression from the past phenotype-based classification to an integrated morphofunctional, etiology-based classification.^19,34

Epidemiology and Familial Cardiomyopathies

The burden of CMP is currently estimated on phenotype-based data: HCM in 1:500 young adults. A revised estimate of the combined prevalence of clinically expressed HCM and gene carriers (at risk for developing the disease phenotype) is placed at about 1 in 200.⁵⁰ The prevalence of nonamyloid primary RCM in adults is unknown; in children, the estimated annual incidence in the United States and Australia is 0.04 and 0.03 per 100,000 children, respectively,⁵¹ and that of DCM and ARVC 1:5000. These values are expected to increase as far as data on patients with early diagnoses in familial CMPs enter scientific literature. In fact, most CMPs have a genetic origin. Familial clustering and gene mutations segregating with the phenotype in families occur in more than 70% of HCM and nonamyloid RCM, and in 50% to 70% of DCM and ARVC.³⁸ The integration of clinical and genetic diagnoses will provide the basis for the molecular epidemiology of CMP. The overall burden of CMP will include patients with clinically overt, symptomatic CMP; asymptomatic patients diagnosed by family screening; and patients with “early” instrumental manifestation of CMP identified by family screening or incidentally in screening programs for sports, driving licensure, and professional suitability.⁵² Several systematic family screening studies demonstrate familial aggregation.^{53,54,55,56,57,58,59,60,61,62,63,64,65,66} For each subtype of CMP, several phenocopies exist, and they should be precisely recognized because each of them may be crucial for risk stratification or be associated with prevention strategies and/or disease-specific treatments.^37,38

Cardiomyopathies as Clinically Heterogeneous, Chronic Diseases

CMPs are clinically heterogeneous diseases, and inheritance pattern (AD in up to 80% of cases; AR, XLR, and maternal in the remaining 20% of familial CMPs), age of onset, and disease progression and severity may differ, even within affected members of the same family.^19,34,37,38 Beyond diagnostic criteria for each type of CMP,⁴⁸ cardiac and extracardiac markers may recur in CMPs caused by defects of different genes. Imaging markers such as LVNC or increased trabeculation recur more commonly in rare CMPs affecting children, such as Barth syndrome. Extracardiac traits can be associated with CMP. Such markers may be ocular (early cataract, retinopathy, palpebral ptosis), auditory (sensorineural hearing loss, dysmorphology of the ears), gastrointestinal (heritable autoinflammatory diseases), renal (spectrum from proteinuria to renal failure), hepatic (liver involvement in systemic storage diseases), musculoskeletal (syndactyly to severe skeletal deformations), or cutaneous/integumental (striae distensae to skin malignancies), or involve the central nervous system (transient ischemic attacks with white matter lesions to cryptogenic stroke), peripheral nervous system (acroparesthesias to overt peripheral neuropathies), or skeletal muscle (mildly increased serum creatine phosphokinase to myopathies/dystrophies).³⁷ Cognitive impairment may also recur in patients with phenocopies of more typical CMPs, such as in Danon disease, lysosomal disorders, or mitochondrial diseases. When integrated in a family cardiomyopathy “mindset,” the pattern of inheritance and both cardiac and extracardiac traits may contribute to phenotype characterization, independently of the number of genes explored in NGS analysis, thus further contributing to the interpretation of genetic results. Each patient diagnosed with CMP introduces a family case study.

Although the clinical onset may coincide with acute heart failure or cardiogenic shock, and past classification included syndromes such as left ventricular apical ballooning syndrome among CMPs,^48,49 typical CMPs are chronic disorders that require lifelong cardiovascular care. Once the diagnosis is consolidated, spontaneous restoration of normal left ventricular size and function in untreated patients does not occur. Current protocols with personalized optimal medical treatments may modify disease progression, extent of left ventricular remodeling, and risk and occurrence of arrhythmias, but cannot not cure affected hearts.

Genetic Heterogeneity

Heritable CMPs are a paradigmatic example of genetically heterogeneous diseases. More than 100 disease or candidate genes have been reported to date as associated with the different subtypes of CMP; several disease genes are not specifically associated with HCM or DCM or ARC, but show genetic overlap.⁶⁷ Accordingly, mutations in genes coding sarcomeric proteins that typically cause HCM may also cause RCM or DCM; similarly, mutations causing DCM (ie, LMNA) may also cause ARC and vice versa. The complex heterogeneity of CMPs and related disease genes is shown in Fig. 9–5A and B.

The Future

Modern clinical workup in CMPs now includes deep phenotyping of the proband, clinical family screening, clinically oriented genetic testing when possible, or genetic screening of large panels of disease and candidate genes. The present challenge is accurate interpretation of the results of genetic testing, which includes both correct assignment of the causative role of the precise mutation to a disease and interpretation of mutations with possible modifier affects. Gene expression studies,⁶⁸ pathology studies of affected hearts testing the expression of a mutated protein,^69,70,71 computational tools, and bioinformatic pipelines contribute to the final interpretation of mutations as being pathologic and disease-causing; this means that, in the absence of the given mutations, the disease does not manifest.⁴⁵ However, no tool can substitute for segregation studies in families or pathologic demonstration of the effects of the mutation in the affected myocardium.⁴⁷ In vitro studies investigating gene expression, protein expression, and structural changes in mutated cells (induced pluripotent stem cell–derived cardiomyocytes) isolated from skin fibroblasts or peripheral mononuclear cells can provide a surrogate alternative to pathologic studies of affected myocardium. Future clustering of CMPs by phenotype, inheritance, and specific cause of disease can (1) generate data for precise clinical-genetic epidemiology and on the natural history of disease, and (2) highlight the need for development of therapies that can specifically target the cause.

Heritable Aneurysmal Diseases

Heritable Thoracic Aortic Aneurysm and Dissection

Heritable thoracic aortic aneurysm and dissection (TAAD) includes more than 40 genetically different disorders (Table 9–1). Syndromic diseases such as MFS, vascular EDSIV, and LDS are characterized by phenotypic traits that usually allow clinical diagnosis,⁶ with genetic testing playing a confirmatory role. TAAD can further occur as an isolated trait or in the context of less-known syndromes.

Genetic, familial TAAD (FTAAD) can be grouped according to the molecular pathway/structure in which disease genes are involved.^6,72 Genes encoding components of the extracellular matrix are associated with MFS (FBN1 gene) and other diseases allelic at the same locus (isolated FTAAD, MAAS, Weill-Marchesani syndrome, familial ectopia lentis syndrome, and geleophysic and acromicric dysplasia)^1,72,73 as well as vascular EDSIV⁷⁴ caused by mutations in the COL3A1 gene. Genes encoding components of the transforming growth factor-beta (TGF-beta) signaling pathway include TGFBR1 and TGBFR2 that cause LDS1 and LDS2 and FTAAD in patients who do not show common traits recurring in LDS1.^72,75 Mutations in the SMAD3 gene (playing its role in the TGF-beta signaling pathway) cause the osteoarthritis-aneurysm syndrome.⁷⁶ Mutations in genes encoding structural components of vascular smooth muscle cells cause FTAAD either as an isolated trait or in association with recurrence of CHD, such as patent ductus arteriosus, bicuspid aortic valve, premature stroke, CAD, and moyamoya disease.^77,78,79 Precise description of the phenotype (TAAD) and of the corresponding disease genes (eg, FTAAD-SMAD3, FTAAD-TGFBR1) incorporates the essential diagnostic information, providing a system to precisely communicate diagnoses.⁶

Bicuspid aortic valve (BAV) is common in the general population (1%). In 25% of cases, it is associated with dilation of the ascending aorta.⁸⁰ BAV-associated aortopathy constitutes a further independent subgroup of aortic diseases, which should be distinguished from that recurring in CHD (such as hypoplastic left heart syndrome, coarctation of aorta, septal defects) and in syndromes such as Andersen-Tawil, DiGeorge, Noonan, LEOPARD, and Turner syndromes.^80,81 Nonsyndromic familial BAV has been associated with mutations in NOTCH1⁸² that encode a single-pass transmembrane receptor with signaling functions, and in GATA5,⁸³ which encodes a cardiac transcription factor. BAV associated with aortic dilatation has also been reported in isolated FTAAD-TGFBR1, FTAAD-TGFBR2, FTAAD-SMAD3, FTAAD-TGFB2, and FTAAD-ACTA2.⁶

In clinical practice, the phenotype-based approach to the diagnosis is distinctly useful for syndromes: most clinicians now recognize MFS patients by their typical skeletal traits, LDS1 patients by their typical craniofacial traits, or EDSIV patients from their skin and face morphology. This diagnostic impact is uniquely beneficial in emergency situations when aortic dissection coincides with the clinical onset of the disease. Additional clinically useful information for patients presenting with emergency aortic dissection is family history, exploring prior similar events or “unexplained” sudden death in relatives.

Genetic Workup

Genetic workup can be either thoracic aortic aneurysm (TAA)–oriented in patients presenting for genetic evaluation after an established diagnosis of arterial aneurysm (aorta or other arteries), or phenotype-based in patients referred for genetic evaluation of skeletal, craniofacial, or ocular traits or syndromes in which TAA may recur. The latter group of patients should undergo 2D echocardiography, wherein the morphology and dimensions of the aortic valve annulus, root, sinotubular junction, ascending aorta, arch, thoracic descending aorta, and abdominal aorta should be systematically annotated. Geneticists involved in TAAD multidisciplinary evaluation should be familiar with normal measures and calculation of corresponding z-scores.⁸⁴ Genetic workup starts with counseling and physical examination of probands; multidisciplinary evaluation can add value to the genetic visit via characterization of multiple phenotypic traits. The pedigree construction may (1) highlight a positive family history for the given syndrome or for isolated TAAD or (2) describe fatal events in relatives.

Diagnosis of Thoracic Aortic Aneurysm

Current guidelines provide detailed information on cardiovascular workup.^85,86 TAA is routinely diagnosed by cardiac/angioimaging, with 2D echocardiography playing a key role. Further imaging investigation includes magnetic resonance or angio-CT scan, either limited to the thorax or extended to the total arterial tree, exploring the entire aorta as well as nonaortic arteries. In syndromes such as EDSIV, aortic dilation is not the rule, whereas aneurysms of muscular arteries are common. Arterial tortuosity is a nonspecific marker but is far more common in LDS than in MFS,⁸⁷ with extreme manifestation in ATS.⁸⁸ Information on nonaortic arteries is essential both as marker of disease and as detection of potentially harmful extra-aortic aneurysms.

Thoracic Aortic Aneurysm in Children

Clinical genetic evaluation should carefully distinguish diseases in which the aortic aneurysm may affect children from those in which the aneurysm develop in young-adult age. Pediatric aortic aneurysms are uncommon in MFS but common in LDS. Other diseases, such as Takayasu arteritis, should be considered, especially when an aortic aneurysm is present as isolated, nonsyndromic trait.⁸⁹ Pediatric nonaortic arterial aneurysms may affect different vascular territories and may contribute to the diagnosis of malignant diseases such as vascular EDSIV.⁹⁰

Inheritance

Most heritable isolated or syndromic TAADs are autosomal dominant diseases (Fig. 9–6). AR and XL TAAD are rare and, in small families, they may appear as sporadic diseases when a unique family member is affected. Typical examples of AR TAAD are ATS, homocystinuria, and cutis laxa type IB. Typical AR syndromes with aortic aneurysm include Alport syndrome and rare lysosomal diseases. Examples of X-linked TAADs include Menkes syndrome and diseases caused by defects of filamin A, which can be both XLR or XL dominant. Aortopathies can occur in patients with CHD, either as monogenic diseases or chromosomal disorders. TAA occurring in children or young and adult patients who do not carry known risk factors for aortic aneurysms should be suspected to have a genetic origin regardless of family history. De novo disease is common in syndromic TAAD, and possible in rare storage diseases such as AFD, in which GB3 accumulates in vascular smooth muscle cells (Fig. 9–7). Two-dimensional echocardiography-based screening of relatives may demonstrate a familial TAAD. In fact, aortic dilation is asymptomatic, unless exerting some compressive effects on closer structures or manifesting with dissection.

Genetic Testing

The decision to proceed to genetic testing relies in part on the family pedigree. If there is no clear phenotype in other family members (all family members appear nonaffected), then the utility of genetic testing is reduced and less commonly pursued. However, isolated TAA can be present in asymptomatic family members who are not aware of their disease. Therefore, a negative family pedigree obtained on the narrative of the proband is not sufficient to exclude a familial TAA. The pedigree can be considered informative after clinical family screening including echocardiographic evaluation of first-degree relatives of the proband.

Genetic testing can be performed by sequencing a unique gene in the instance of a strong clinical diagnostic hypothesis. Alternatively, large panels of disease genes and exome sequencing are used to identify mutations in known disease genes or novel candidate/disease genes.^91,92,93,94 Depending on the disease gene, the interpretation of results may confirm the clinical diagnosis or play a diagnostic role in isolated, nonsyndromic TAAD. This highlights the need of deep phenotyping in isolated TAAD in order to identify traits specifically recurring in apparently nonsyndromic TAAD associated with mutations in different genes, so that physicians are able to ascertain markers of disease or traits predicting the occurrence of the aortic aneurysm. A representative example is iris focculi, which may recur in families with ACTA2-TAAD.^35,95 Prenatal diagnosis is now offered on a regular basis to couples in which one parent is affected by MFS.⁹⁶ Noninvasive prenatal and preimplantation diagnosis can be an alternative to a conventional prenatal diagnosis for couples that do not accept the risk of pregnancy loss.⁹⁷

Genotype-phenotype correlation studies have been performed in several syndromic TAADs with the major aim of distinguishing highly malignant diseases from milder phenotypes. MFS is the most widely investigated disease; nosology has changed over time, from the pre-genomic era, to the last 2010 revision,⁹⁸ in which genetic testing entered as a major diagnostic criterion. Genetic testing is recommended in newly suspected MFS, especially when two systems are involved, with at least one major system affected.⁹⁹ Patients who carry FBN1 mutations and demonstrate only one major clinical criterion or only minor clinical criteria in one or more organ system represent 5% of the adult series.¹⁰⁰ The majority of clinical manifestations of MFS increase with age.¹⁰¹ Infant carriers of mutations in the neonatal exons demonstrate severe phenotypes¹⁰²; in children less than 1 year of age, a shorter survival was associated with presence of valve insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26.¹⁰³ A higher risk of aortic dissection is reported in male patients.¹⁰⁴

The Impact of Precise Genetic Diagnosis

In the past 10 years, it has been demonstrated that risk stratification for aortic dissection may vary based on the different subtypes of FTAAD and that preventive surgery should be planned considering both the individual patient and the disease-specific risk.⁸⁵ In addition, the proposed role of TGF-beta in aneurysmal diseases, and FBN1 mouse models treated with anti-TGF-beta antibodies or drugs acting on TGF-beta opened up the possibility of exploring the effects of angiotensin receptor blockers (ARBs) in patients with MFS. Many clinical trials comparing the role of ARBs with beta-blockers¹⁰⁵ have recently been concluded and others will conclude in the near future (Table 9–2).^{106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127} Based on results achieved to date, patients with MFS and aortic root dilation should receive medical therapy, with either beta-blockers or ARBs or both. Medications seem to be more effective at reduction of aortic root z-score in younger subjects, which suggests that medical therapy should be prescribed even in the youngest children with early/mild aortic dilation. For patients without aortic dilation, indications for medical treatment are less clear. In patients with severe and/or progressive aortic dilation the combination of a beta-blocker and ARB should be considered, although current trial results are mixed with respect to the efficacy of combination therapy versus monotherapy.

Independent of the results, the message from these studies is the novel impact of precise diagnosis on the potential development of personalized, disease-oriented treatment of heritable aneurysmal diseases.

Pulmonary Hypertension

Definition and Classification

Pulmonary arterial hypertension (PAH) is a rare, life-threatening disease, affecting between 1 to 2 per 100,000 and 1 per 1 million people¹²⁸ (see Chap. 74). In the 2016 ESC guidelines, pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure—at least 25 mm Hg at rest as assessed by right heart catheterization.¹²⁹ Current clinical classification is based on the principles of similarities in pathobiology, clinical features, and therapeutic options.¹³⁰ More than 40 different diseases are divided into 5 groups (updated classification, Nice, 2013):

1. Group 1: idiopathic, heritable, drug-induced PAH, CHD with pulmonary hypertension, pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis. This includes chromosomal deletion syndromes such as Williams-Beuren syndrome (deletion 7q11.23) and Alagille syndrome (deletion 20p11-2) as well as monogenic diseases such as Keutal syndrome and cutis laxa, in which peripheral pulmonary artery stenosis may occur either as isolated defects or in association with other congenital heart defects.

2. Group 2: pulmonary venous hypertension or PAH caused by left heart disease

3. Group 3: PAH caused by lung diseases and/or hypoxia

4. Group 4: chronic thromboembolic PAH (CTEPH)

5. Group 5: miscellaneous disorders that can affect the pulmonary vasculature with unclear and/or multifactorial mechanisms.

The causes can be genetic in primary PAH, group 1, and group 5.

Genetic Workup and Assessment of Disease-Specific Risk Factors

Genetic causes are well recognized in several forms of PAH. Accordingly, the diagnostic workup should systematically include counseling and, in case of monogenic diseases, clinical family screening, and cascade genetic testing. Genetic counseling explores personal and family medical history as well as exposure to known toxic agents and drugs, followed by genetic testing as recommended by scientific societies.¹³¹ Disease-specific risk factors are classified as definite, likely, or possible on the basis of the strength of their association with PH and their probable causal role^130,132 (Table 9–3). A definite association is acknowledged in the case of appetite suppressants, or for drugs demonstrated as being associated with PAH in multicenter epidemiological studies. A likely association is considered when demonstrated in a single-center case-control study or multiple case series, or when clinical and hemodynamic recovery occurs after cessation of exposure (ie, dasatinib-induced PAH). The association is defined as possible for drugs with similar mechanisms of action as those in the two aforementioned categories, but have not yet been systematically studied, such as those used to treat attention deficit disorders. Genetic counseling should also explore autoimmune diseases, infections such as human immunodeficiency virus (HIV), possible parasitic diseases, exposure to radiation, living environment (high altitude), chronic renal diseases, sarcoidosis, and prior splenectomy. In patients with CTEPH, the investigation should include history of venous thromboembolic events (when known) and thrombophilic disorders.^133,134 The pattern of inheritance is autosomal dominant in most patients with familial pulmonary hypertension; however, rare pulmonary veno-occlusive forms are inherited as recessive traits and may appear as sporadic, especially in small or noninformative families. Accordingly, genetic counseling, and eventually genetic testing, should be offered to all patients diagnosed with PAH (group 1) and pulmonary hypertension of unclear origin (group 5).

Genetic Testing

More than one disease gene has been identified in primary pulmonary hypertension (PPH)^128,135 (Table 9–4). Genetic testing in probands can be clinically guided or performed through the screening of multigene panels by NGS. A clinically oriented approach is feasible for familial autosomal dominant PPH, in which mutations of bone morphogenetic protein receptor 2 (BMPR2) recur in up to 80% of patients and families. BMPR2 plays a role in the pathway of BMP and is a member of the TGF-beta superfamily that regulates cell growth, differentiation, apoptosis, and development. Less common disease genes, such as SMAD9, play a role in the same BMP pathway as downstream modulators of the BMP signaling pathway and cause a phenotypically similar, autosomal dominant PPH. Other disease genes, such as ALK-1 and endoglin (ENG), play a role in the TGF pathway; these genes account for a minority of familial PPH, which is a major trait of Osler–Weber–Rendu disease. Defects in other rare disease genes, such as CAVEOLIN 3 (CAV3), or genes coding ion channels, such as KCNH3, result in a similar phenotype, but via different mechanisms. Novel candidate genes include TOPBP1¹³⁶ and CYP1B1.¹³⁷ Pulmonary veno-occlusive hypertension is allelic at the PPH1 locus (BMPR2), whereas the recessive form is caused by mutations in EIF2AK4.¹³⁸ Finally, group 5 PAH includes a variety of acquired and heritable diseases such as the AD lymphangioleiomyomatos¹³⁹ and lysosomal storage diseases such as glycogen storage disease types 1 and 3^140,141 and Gaucher disease type 1.^142,143

Interpretation of the Results of Genetic Tests

The type of mutation facilitates the interpretation of BMPR2 testing results. Most mutations are truncation-predicting defects (frameshift, nonsense, splice site) ending in haploinsufficiency.¹³⁵ In carriers of missense mutations, family segregation studies, in silico analysis, and eventually pathologic studies (when lung samples are available) may contribute to clarify their role. Genetic tests should be expanded to all probands presenting with “idiopathic” PPH; up to 20% of patients with apparently sporadic PPH carry BMPR2 mutations.

The segregation analysis of the genotype with phenotype can be complicated by incomplete penetrance because affected members of the same family may not show the phenotype at time of screening; regular clinical monitoring should be scheduled for clinically unaffected but genetically affected family members. Phenotype expression may be age-dependent or may be influenced by exposure to environmental factors. A double-hit hypothesis has been proposed to explain the variable clinical manifestations of the disease. The hypothesis of anticipation of the phenotype in younger members of the same family does not have corresponding molecular mechanisms. Current knowledge regarding the molecular basis of PPH1 does not include evidence of triplet expansion, and recent longitudinal studies do not seem to confirm this hypothesis.¹⁴⁴ Finally, incomplete penetrance can be a result of incomplete genotyping; the spectrum of disease and modifier genes potentially involved in PPH are far from being fully elucidated.

Translational Impact

Clinical genetics with counseling and pedigree construction, search for known risk factors and annotation of novel potential risk factors, family investigation, and genetic testing are currently translated in the clinical setting. Clinical attention to PAH is encouraged by the availability of new medical treatments (endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, soluble guanylate cyclase stimulators, and prostanoids) that continue to be tried in patients with idiopathic, heritable, drug-induced, and connective tissue disease-associated PAH. Genetic workup significantly contributes to precise diagnosis.

Inherited Atrial Diseases

Genetic Atrial Diseases: Beyond Atrial Fibrillation

Heritable atrial diseases include rare atrial CMPs, AR or AD sick sinus syndrome, rare novel syndromes with extracardiac involvement, and a certain proportion of lone atrial fibrillation (AF). The aim of this section is to highlight the genetic workup of rare heritable atrial diseases and familial lone AF (see AF in Chap. 83).

Atrial Dilated Cardiomyopathy

ADCM is a rare AR disease characterized by clinical onset in adulthood, biatrial dilatation up to giant size, early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill, thromboembolic complications, stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease, and severely decreased levels of atrial natriuretic peptide. The disease is caused homozygous mutations in the natriuretic peptide precursor A (NPPA) gene; heterozygous carriers are healthy and demonstrate normal levels of atrial natriuretic peptides.¹¹ Phenotypically similar, adult-onset phenotypes have been reported in one Indian case,¹⁴⁵ two Australian patients,¹⁴⁶ and, more recently, children with isolated right atrial dilation.¹⁴⁷ Similar atrial disease and isolated atrial amyloidosis in three Japanese siblings¹⁴⁸ suggest a recessive inheritance, and the possible contribution of atrial amyloid deposits to the pathological substrates of atrial CMPs. In the past, these diseases were described as idiopathic atrial dilation or congenital atrial malformations.^149,150 A precise diagnosis influences decision on treatments such as ablation for arrhythmias and early anticoagulation that should be initiated in patients with atrial dilation regardless of the arrhythmias. When the disease is unrecognized, stroke can coincide with disease onset.

Sick Sinus Syndrome

Sick sinus syndrome (SSS) is clinically characterized by sinus bradycardia, sinus arrest, chronotropic incompetence and susceptibility to atrial arrhythmias.¹⁵¹ SSS can be sporadic, such as the common SSS observed in older persons,¹⁵² or familial, typically manifesting in young patients. Familial SSS are clinically and genetically heterogeneous diseases, either AD or AR. The onset of AR SSS (SSS1, MIM #608567) may occur in childhood and adolescence.^{153,154,155,156,157} It is caused by mutations in SCN5A gene, which encodes the α-subunit of the cardiac Na⁺ channel. In small families, the disease may appear as sporadic; however, the young age of patients and the absence of other cardiac diseases that may explain the phenotype are by themselves sufficient to refer probands and families for genetic counseling. Clinical family screening demonstrates the absence of manifestations in parents. Parental consanguinity or origin of parents from geographic isolates may contribute to suspect AR inheritance. Genetic testing demonstrating homozygous mutations or compound mutations in the SCN5A gene is uniquely useful to conclude the diagnostic workup.¹⁵⁸ The AD SSS (SSS2, MIM #163800) is caused by mutations in the HCN4 gene that codes for hyperpolarization activated cyclic nucleotide-gated potassium channel.¹⁵⁹ Heterozygous mutations have been identified in patients with SSS complicated by life-threatening arrhythmias¹⁶⁰ and in familial asymptomatic sinus bradycardia.¹⁶¹ The genetic diagnosis of SSS contributes to identify at-risk family members, to schedule monitoring for prevention of arrhythmias, and to support decisions for ablation of atrial arrhythmias or PM implantation.

Rare Novel and Known Syndromes: Cohesinopathies

Cohesinopathies are disorders caused by mutations in subunits or regulators of cohesin.¹⁶² They may commonly affect the heart and manifest with arrhythmias and/or CHD. Atrial arrhythmias recur in chronic atrial and intestinal dysrhythmia (CAID) syndrome, a recently described AR disorder. CAID is clinically characterized by deregulation of the cardiac sinus node leading to SSS and of gastrointestinal motility resulting in chronic intestinal pseudo-obstruction (CIPO).¹⁶³ Both traits can represent distinct disorders associated with mutations in genes known to cause either SSS or CIPO. However, when SSS and CIPO coexist, the disease-causing gene is Shugosin-like 1 (SGOL1, MIM *609168), which has been recently identified in 16 French Canadians and 1 Swede; the gene encodes a component of the cohesin complex (made up of SGO1 and SGO2) that protects centromeric integrity.¹⁶³ Atrial arrhythmias do not seem to be common in other cohesinopathies, such as Cornelia de Lange syndrome (CDLS) in which CHD recur in up to 30% of cases¹⁶⁴; left ventricular dilation and hypertrophy, right ventricular CMP, and sudden death in CDLS have been reported in autopsy series¹⁶⁵ or in patients demonstrating HCM.¹⁶⁶ CDLS is a genetically heterogeneous disease entity, with five associated genes, all of which are active in the cohesin complex.¹⁶⁷

The precise diagnosis of CAID has clinical implications for affected children and young adults, not only for atrial arrhythmias but also for treatments of CIPO, including both prokinetic agents used to relieve symptoms caused by gut dysmotility (ie, arrhythmogenic effect of cisapride)^168,169 and nonopioid drugs used to control abdominal pain.¹⁷⁰

Atrial Fibrillation

AF is the most common arrhythmia (1.5% of the general population), affecting health and quality of life. Lone AF accounts for about 5% to 10% of all AF. AF can be sporadic or familial^171,172; about 30% of patients with AF have a positive family history,^173,174 and individuals with at least one parent with AF have a relative risk of AF of 85%.¹⁷³ Genetic studies are rapidly progressing, and numerous disease genes and chromosomal loci have been identified to date in familial AF¹⁷⁵ (Table 9–5).

The role of clinical genetics involves deep phenotyping patients presenting with lone AF to exclude presence of other traits or diseases that can explain the arrhythmia. In fact, some of the genes that have been linked to AF may also cause different cardiac and noncardiac diseases. In other words, AF can represent one of the early manifestations of genetic CMPs. Family studies should demonstrate that other affected members do not exhibit CMPs or other cardiac diseases; the distinction between lone familial AF versus AF complicating other genetic heart diseases prevents incorrect assignment of a causative role for AF to genes that cause CMPs in which AF may recur as part of the evolving phenotype.¹⁷⁶ A typical example is AF in patients with cardiolaminopathies. A systematic screening of LMNA in a cohort of 268 unrelated patients with idiopathic forms of familial and sporadic AF identified a unique, possible but nonconfirmed mutation, thus excluding this gene as a candidate for lone AF.¹⁷⁷ Disease genes identified by linkage analysis in well-phenotyped families have been confirmed both as cause of familial AF^178,179,180 and of different heritable atrial diseases (NPPA).¹¹ Genes such as SCN5A that cause long QT syndrome (LQTS), short QT syndrome (SQTS), or Brugada syndrome may also cause AF, and long-term follow-up of mutation carriers is necessary to exclude other arrhythmogenic phenotypes or explore why the same mutations may manifest different arrhythmogenic phenotypes.

Precision Diagnosis of Atrial Diseases

Genetic AF is an expanding area of precision cardiology but requires family screening and monitoring to confirm a disease gene for AF. Segregation studies are complicated by the need for long-term follow-up or recording systems to clinically identify family members at risk of developing AF. Paroxysms of AF can be clinically silent and, unless an ECG recording system is implanted, clinically silent episodes of AF can be missed. Clinical surveillance can reveal silent AF episodes, thus contributing to genotype-phenotype correlation studies, preventive treatments, and elucidation of the role of genetic mutations in AF. Electroanatomic mapping in patients with AF is now contributing to the characterization of structural fibrotic changes observed in patients with heritable atrial diseases.¹⁸⁰ Recently, the term fibrotic atrial cardiomyopathy has been introduced to describe the fibrotic substrate observed in patients with AF.¹⁸¹ Unraveling whether fibrosis is the cause or effect in heritable AF may contribute to treatment decisions.

Inherited Channelopathies and Life-Threatening Ventricular Arrhythmias

Cardiochannelopathies encompass a large, genetically heterogeneous group of electrical abnormalities that can be associated with unexpected sudden death.^182,183 The majority of disease genes encode cardiac ion channels or proteins interacting with ion channels or involved in ion flux and metabolism (Table 9–6).^182,183 Genetic workup includes clinical evaluation, genetic testing, and post-test counseling. Genetic teams, including clinicians, geneticists, genetic counselors, basic scientists, and pharmacologists, should evaluate the phenotype, age, gender, family and drug history, comorbidities, patient preferences, and therapeutic alternatives before proceeding to genetic testing.^184,185 Patients and families are addressed to genetic counseling for (1) incidental observation of prolonged or short QT interval or Brugada pattern or early repolarization in ECG screening studies (eg, sport, professionals, army), (2) unexplained syncope, (3) resuscitated cardiac arrest (aborted sudden death), or (4) sudden death in a family member. The last condition represents the most complex diagnostic challenge when the DNA of the victim has not been preserved and medical records are not available. In this case, clinical family screening (ECG, 2D-echocardiography, 24-hour Holter monitoring) is the first step to establish whether relatives of the victim demonstrate ECG abnormalities or unperceived arrhythmias. The major groups of channelopathies associated with risk of sudden death include diseases that lengthen the QT interval—Brugada syndromes and catecholaminergic polymorphic ventricular tachycardia (CPVT). These disorders are extensively reviewed in Chapters 79, 80, and 91. In this section, we briefly summarize major arrhythmogenic cardiochannelopathies, inheritance, disease genes, and phenotypes to provide further information for genetic counseling and testing.

Long QT Syndrome

LQTS is an autosomal dominant arrhythmic disease characterized by a prolonged QT interval on resting 12-lead surface ECG in the absence of structural heart disease. Inheritance is AR in the rare Jervell and Lange-Nielsen syndrome. Patients with LQTS may remain asymptomatic during their entire life or manifest symptoms caused by ventricular arrhythmias; syncope, aborted cardiac arrest, or sudden cardiac death can be the first manifestation of the disease.¹⁸⁶ Although many genetically different types of LQTS are known, 90% of cases are associated with mutations in KCNQ1 encoding Kv7.1 (LQT1), KCNH2 encoding Kv11.1 (LQT2), and SCN5A encoding Nav 1.5 (LQT3).¹⁸⁷ In LQT1, T waves are broad-based and symptoms recur during exercise; in LQT2, T waves are low-amplitude, notched or biphasic, and symptoms are induced by acoustic triggers; and in LQT3, narrow-based T waves are preceded by long isoelectric segment and symptoms occur during rest.^187,188 The remaining 10% of pathogenic mutations occur in genes encoding other ion channels or in genes encoding proteins interacting with ion channels (see Table 9–6).

The diagnosis of LQTS is based on consensus criteria.¹⁸⁹ A scoring system allows for the summation of points assigned to ECG findings at baseline and after exercise stress, evidence of torsade de pointes, history of syncope, congenital deafness, family history and members with LQTS, and unexplained sudden cardiac death (SCD) below age 30 years among immediate family members.^190,191 A score equal to or greater than 3.5 points is the diagnostic cutoff, with a greater than 70% probability of identifying pathogenic mutations when the score is equal to or greater than 4. Genotype is not included in the score. The risk of life-threatening arrhythmias and events is high in (1) patients with QTc interval equal to or greater than 500 ms and a history of syncope, (2) LQT1 associated with missense mutations in residues of the cytoplasmic loop of the protein, and (3) females with LQTS2 and males with pore-loop missense mutations.^192,193,194

Treatment includes beta-blockers (propranolol and nadolol) whose effectiveness may vary in the different subtypes of LQTS: highest for LQT1, less effective in LQT2 and LQT3.¹⁹⁵ Mexiletine and ranolazine can be used adjunct to beta-blockers in LQT3.^196,197 Implantable cardioverter defibrillator (ICD) therapy is indicated in patients who suffered syncope while treated with beta-blockers and in those with very long QTc (0.550-ms) intervals. Left cardiac sympathetic denervation is a possible added therapy for severely affected patients who are refractory to beta-blocker therapy.¹⁸⁹ For drugs to be avoided by patients with long QT syndrome, see https://crediblemeds.org/pdftemp/pdf/DrugsToAvoidList.pdf.

Short QT Syndrome

SQTS is an inherited arrhythmic disease associated with increased risk of AF, ventricular tachycardia/ventricular fibrillation (VT/VF), and SCD.¹⁹⁸ Current estimates indicate a prevalence of 0.02% to 0.1% in the adult population and 0.05% in children and adolescents.¹⁹⁹ The diagnosis is made when the QT interval is equal to or less than 330 ms in the absence of tachycardia or bradycardia. Gain-of-function mutations in three genes encoding potassium channels, KCNQ1, KCNH2, and KCNJ2, have been associated with SQTS. Given the high risk of SCD, prophylactic ICD therapy is appropriate; adjunctive pharmacological therapy such as quinidine that prolongs QT interval is beneficial in a subset of these patients.^189,200

Brugada Syndrome

Brugada syndrome is an AD arrhythmogenic disease characterized by ST-segment elevation with negative T wave in the right precordial leads in the absence of structural cardiac abnormalities.^201,202 Although clinical manifestations include syncope or cardiac arrest caused by VF, the majority of patients remain asymptomatic lifelong. The disease burden is estimated to range from 5 to 20 individuals in 10,000, with higher prevalence in Asian populations. Although the mean age of patients manifesting life-threatening arrhythmias is around 40 years, arrhythmic events can occur at any age; arrhythmias typically occur while sleeping or at rest, after heavy meals, or during episodes of fever.^202,203 To date, numerous genes have been associated with Brugada syndrome, but pathogenic mutations are identified in about 30% of patients, with SCN5A gene accounting for the majority of cases and other genes accounting for about 5% of genotyped cases.²⁰⁴ Overlap phenotypes (LQTS, SQTS and Brugada syndrome) are possible in affected members of the same families, given that the disease gene can be the same (eg, SCN5A).²⁰⁵ A recent “oligogenetic inheritance” hypothesis postulates that mutations in more than one disease gene are needed to induce a clinical phenotype.²⁰⁶ In patients with equivocal baseline ECG pattern as unique evidence of possible disease, ajmaline provocation tests can be performed.¹⁸⁹ Other diseases/factors potentially manifesting a Brugada-like ECG patterns (IHD, hyperkalemia, hypercalcemia, arrhythmogenic right ventricular dysplasia, myocarditis, mechanical compression of the right ventricular outflow tract, or pulmonary embolism) should be excluded. In symptomatic patients, risk stratification includes history of VT/VF, syncope and spontaneous coved-type ST-segment elevation. In asymptomatic patients, risk stratification includes male gender and fragmented QRS, which is a marker of conduction abnormality and a predictor of prognosis.²⁰⁷ The first-line therapy is ICD in patients with a history of VT/VF or syncope.¹⁸⁹ Administration of drugs that can trigger type 1 ECG changes and arrhythmias (www.brugadadrugs.org) should be avoided. For phenocopies, see www.brugadaphenocopy.com.

Catecholaminergic Polymorphic Ventricular Tachycardia

CPVT is a rare disease (1:10,000) that typically presents with syncope or cardiac arrest triggered by exercise or emotion in children/adolescents.^27,208 Mortality is high in affected, unrecognized, and untreated patients. The baseline ECG is normal but exercise induces the polymorphic ventricular arrhythmias; a few patients may demonstrate bidirectional ventricular tachycardia.^208,209 The disease is genetically heterogeneous. CPVT1 (60%–70%) is AD and caused by mutations in the gene RYR2 gene, and CPVT2 is AR and is associated with mutations in the cardiac calsequestrin gene (CASQ2).²¹⁰ Both RYR2 and CASQ2 are involved in myocyte calcium homeostasis.²⁰⁹ Less common disease genes include KCNJ2 (CPVT3), calmodulin (CALM1), and triadin (TRDN).^211,212 Risk factors for arrhythmic events include young age, male gender, history of cardiac arrest, occurrence of arrhythmias while taking beta-blockers, and mutation in the c-terminus of the RYR2 gene.²¹³ All genotyped patients should be treated with beta-blockers at the highest tolerable dose, adding flecainide when beta-blockers do not control arrhythmias. In severely affected patients, ICD discharge can induce catecholamine release, causing ventricular storms.^214,215

Overall, geneticists actively involved in counseling and testing patients with suspected cardiochannelopathies and potential risk of life-threatening ventricular arrhythmias should be part of multidisciplinary specialized teams and be cautious in the interpretation of the role of genetic variants identified by genetic testing. In fact, family segregation studies, which usually strongly contribute to support causality of mutations, may be limited by the difficult phenotype characterization of asymptomatic and “ECG-negative” relatives who may or may not manifest traits typically recurring in these diseases.

Tumors of the Heart and Genetics

Rare and Genetic Tumors of the Heart

Tumors of the heart are rare (see Chap. 101), with autopsy incidence ranging from 0.001% to 0.03%, including all primary benign and malignant neoplasms. In the revised World Health Organization 2015 classification, they are grouped as benign tumors, tumors of uncertain biologic behavior, germ cell tumors, and malignant tumors.²¹⁶ Among all, myxoma, rhabdomyoma, fibroma, and some tumor-like histiocytoid diseases of the heart may be present in the context of syndromes suspected based on their clinical presentation and confirmed by genetic testing.

Cardiac myxoma occurs in Carney complex and accounts for up to 10% of all cardiac myxomas,²¹⁷ but it may also occur as isolated neoplasm. Carney complex is clinically characterized by pigmented lesions of the skin and mucosa, recurrent cardiac, cutaneous and other myxomas, and multiple endocrine tumors.²¹⁸ Patients are usually younger than those with sporadic myxoma, and there is no female predominance. Carney complex type 1 is caused by mutations in the cyclic adenosine 5′-monophosphate-dependent protein kinase (PRKAR1A gene), whereas Carney complex type 2 has been mapped at 2p16 locus, but the gene is still unknown. A variant of Carney complex with distal arthrogryposis is associated with defects in the MYH8 gene. The diagnosis is made in the presence of (1) two of the major criteria confirmed by histology, imaging, or biochemical testing or (2) one major criterion in addition to the presence of one supplemental criterion.^219,220 Pancreatic acinar cell carcinoma, adenocarcinoma, and intraductal pancreatic mucinous tumors have been reported in as many as 2.5% of patients.²²¹ Genetic counseling and testing are part of the diagnostic workup.

Rhabdomyoma typically occurs in patients with tuberous sclerosis, an AD disorder that is clinically characterized by the triad of neurofibromatous lesions, mental slowing, and cutaneous lesions.²²² Multiple rhabdomyomas are found in about half of children affected by tuberous sclerosis. The disease is caused by mutations in tumor suppressor genes [TSC1 coding amartin (9q34) and TSC2 coding tuberin (16p 13.3)] that also cause lymphangioleiomyomatosis and pulmonary hypertension. The inactivation of the tuberous sclerosis complex genes, TSC1 and TSC2, and the activation of the mammalian target of the rapamycin (mTOR) pathway enhance cell proliferation and migration, lymphangiogenesis, metastatic spread, sex steroid sensitivity and deregulated autophagy.²²³ The mTOR activation provides the basis for target therapy with mTOR inhibitors.²²⁴

Cardiac fibroma recurs in the AD basal nevus syndrome or Gorlin syndrome, causally linked with mutations in the tumor suppressor protein encoding patched Drosophila homolog 1 (PTCH1) gene.^225,226 The PTCH1 transmembrane protein represses transcription in specific cells of genes encoding members of the TGF-beta and Wnt families of signaling proteins. The penetrance of the PTCH1 mutations is complete, but the clinical phenotype may vary, including skeletal abnormalities and increased risk of tumors—in particular, desmoplastic medulloblastoma. The diagnosis and management requires multidisciplinary collaboration because the disease is multisystemic. Genetic counseling for parents of affected children reveals the complex association of phenotypic traits, the relevance of early diagnosis, and the need for scheduled multidisciplinary monitoring of and decision making about the multiple lesions.²²⁷

Purkinje cell hamartoma, or cardiac hamartoma, also termed histiocytoid cardiomyopathy (or oncocytic cardiomyopathy), is an XL dominant disease. Endocardial or myocardial nodules that may involve the sinoatrial and atrioventricular nodes characterize the macroscopic view. Histologically, myocytes appear round and vacuolated and demonstrate conspicuous numbers of mitochondria. The disease has recently been associated with the de novo nonsense mutations in the NADH ubiquinone oxidoreductase subunit B11 gene (NDUFB11) in two unrelated female patients and with two de novo missense mutations in NDUFAF2 and NDUFB9 in a third female patient.²²⁸ Although rare, diseases associated with mutations in NDUFB11 are of special interest because they represent one of the very few examples of XL dominant diseases (ie, linear skin defects with multiple congenital abnormalities 3, MIM #300952), and because of the possible synergy with additional mtDNA variants.

Somatic mutations in cardiovascular tumors are emerging as novel potential contributors to identify therapeutic targets. Target next-generation sequencing (tNGS) of oncogenes and tumor-suppressor genes in primary cardiac angiosarcomas have demonstrated that the p.R707Q mutation in phospholipase C gamma 1 (PLCG1) constitutively activates the protein PLCγ1 and provides an alternative way of activation of kinase insert domain receptor (KDR)-PLCγ1 signaling in angiosarcomas. This evidence opens novel avenues for VEGF/KDR targeted therapies.²²⁹ Intimal sarcomas of the heart have demonstrated mouse double minute 2 homolog (MDM2) gene amplification and overexpression of the MDM2 protein, again raising the possibility of targeted therapies.²²⁹

Identification of the Genetic Basis Facilitates Novel Treatment Strategies

Genetic tumors of the heart, both isolated or, more commonly, part of complex syndromes, can be clinically recognized by family screening and precisely diagnosed by testing corresponding disease genes. The precise diagnosis, including the pathology and the constitutive and somatic genetic defects, provide novel basis for targeted treatments. Clinical implications include scheduling of surgery for excising potentially recurring tumors (ie, atrial myxoma in Carney complex) especially in children, introducing mTOR inhibitors such as rapamycin for control of lymphangiogenesis, and tailored monitoring and interventions in syndromes with multiple tumors such as Gorlin syndrome. Somatic mutations in sarcoma cells can drive novel anticancer therapies in primary cardiac malignancies.

Heritable Autoinflammatory Diseases

Diseases That Should Be Included in the Differential Diagnosis of Inflammatory Heart Diseases

The heart can be involved in heritable autoinflammatory disorders (HAIDs). HAIDs are a group of monogenic diseases characterized by exaggerated inflammatory response through uncontrolled production of cytokines, which cause recurrent episodes of inflammation, followed by symptom-free periods of variable length.^174,230 HAIDs usually manifest with periodic fever syndromes. Cardiac involvement may occur as direct effect of the systemic inflammatory process. The onset may mimic infective pericarditis, myocarditis, or myocardial inflammation with fibrosis; in clinical practice, these conditions often remain labeled as idiopathic. Vascular involvement is rare.²³¹ Myocardial infection is usually the first diagnostic hypothesis in patients presenting with fever and either chest pain and normal coronary arteries, arrhythmias, or heart failure. Differential diagnosis now includes possible genetic origin of inflammatory heart disease.

Heritable Autoinflammatory Disorders: An Expanding Clinical Field

The number of clinically and genetically characterized autoinflammatory diseases is expanding. The feasibility of precise diagnoses and the increasing number of drugs specifically targeting key molecules that mediate tissue inflammation and damage are becoming vastly important in this field. HAIDs demonstrate the nonobligate relationship between cardiac inflammation and infections, and possible targeted treatment once patients have a precise diagnosis. Table 9–7 lists major diseases, genes, and organ involvement; for some of them, the type of cardiac involvement is known, whereas for others, cardiac involvement is not yet reported. Detailed description of all of these diseases goes beyond the scope of this section. We shortly discuss familial Mediterranean fever (FMF), which is the paradigmatic example of HAID demonstrating cardiac involvement (see also Chap. 61).

Familial Mediterranean Fever

FMF is the most common familial autoinflammatory monogenic disease. It was first described as an autosomal recessive disease recurring in Eastern Mediterranean populations (Fig. 9–8).²³² The disease is caused by mutations in the MEFV gene that encodes pyrin, a component of the cellular inflammasome. After the identification of the MEFV gene, the genetic-driven name pyrin-associated periodic fever syndrome (PAPS) was proposed. Analogous to CMPs that have been recently reclassified integrating the phenotype-based, descriptive diagnosis with the specific cause of each subtype of CMP,¹⁹ a precise nosology of HAIDs will be especially beneficial in the incoming era of precision cardiology, especially when target treatments are available and effective. PAPS is inherited as an AR disease^233,234 (see Fig. 9–1). Milder disease course, later onset, and less frequent and less severe inflammatory attacks may recur in patients who carry genetic variations that are not associated with the classical phenotype. Systematic sequencing of the whole MEFV exons showed that homozygous mutations recurred in 20% to 30% of patients with FMF.²³⁵ Heterozygous carriers of MEFV mutations can develop a different inflammatory AD disease^236,237 or manifest the phenotype in the setting of exogenous triggers (ie, infections),²³⁸ suggesting a double-hit hypothesis.^239,240,241

Genetic Diagnosis and Recommendations

Although the first recommendation for genetic diagnosis of FMF states that, “FMF is a clinical diagnosis, which can be supported but not excluded by genetic testing” (level of evidence B), genetic testing and genotype-phenotype correlations are part of the modern diagnostic workup of PAPS. Of the eight recommendations provided by experts, level A evidence is for asymptomatic individuals homozygous for p.(Met694Val) mutations; these individuals should be evaluated and followed closely so that appropriate therapy is considered.²⁴²

Multifactorial Cardiovascular Diseases

Genetics in Multifactorial Diseases

Most cardiovascular diseases have a multifactorial origin. Common examples include atherosclerosis, CAD, heart failure syndrome, hypertension, dyslipidemia, and diabetes. Each of them results from a complex interplay between environmental and genetic factors. The baseline risk in individuals with positive family history of MI, diabetes, hypertension, or dyslipidemia includes nonmodifiable factors (family history, gender, age).²⁴³ Traditional risk factors and combinations thereof, age of onset and duration and treatments, are largely modifiable, even in heritable diseases such as AD familial hypercholesterolemia.²⁴⁴ The risk of events (ie, acute MI) includes the global risk of the underlying disease (atherosclerosis) and the event-related risk that incorporates factors involved in local and systemic inflammation and arterial thrombosis.²⁴³ The impact of positive family history varies in different multifactorial diseases. It is higher for CAD²⁴⁵ and lower for “heart failure syndrome,”²⁴⁶ in which risk stratification includes the primary cause of heart disease, the remodeling pathway, and the responsiveness to therapy.

Coronary Artery Disease as a Paradigm of Multifactorial Disease

Scientific and clinical achievements over the past 50 years (the post-Framingham era of cardiology) are tremendous. Identification of risk factors; prevention programs; drugs such as aspirin, statins, RAS inhibitors, and beta-blockers; and interventional procedures have modified the epidemiology and outcome of many multifactorial cardiovascular diseases.²⁴⁷ Primary and secondary prevention programs as well as better diagnosis and treatments have resulted in increased survival, better quality of life, and increased life expectancy. In developed countries, the disease is decreasing,²⁴⁸ whereas in developing countries, the disease is increasing.²⁴⁹ Future contribution of genetics is expected to implement personalized precision medicine, which aims at tailoring risk, prevention, and treatments on individual clinical profiles and needs.²⁴⁹

The completion of the Human Genome Project,²⁵⁰ the sustainable sequencing of large panels of genes or whole exome/genome sequencing, promises progressing individual genotyping and genetic characterization of individuals at risk (eg, association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate). Together, these variants explain approximately 10.6% of CAD heritability.²⁵¹ The study confirms that the four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. A recent GWAS meta-analysis, including about 185,000 CAD cases and controls and interrogating 6.7 million common (minor allele frequency [MAF] > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants, confirmed most known CAD-associated loci and further identified ten new loci (eight additive and two recessive) that contain candidate causal genes, newly implicating biological processes in vessel walls. The analysis shows that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.²⁵² Because loci identified by GWAS explain less than 10% of the genetic variance in CAD (90% of CAD heritability remains to be explained), systems genetics-building network models of relevant molecular processes can also capture environmental and modifiable influences on CAD. This combination is likely to be a lot more powerful for characterization of individuals with CAD than just DNA alone.²⁵³

Paradoxically, as far as new genetic information enters the scientific world, the translation calls for clinical skill, deep phenotyping, and family studies. New endovascular imaging and imaging markers (coronary artery calcium score, carotid intima-media thickness, and ankle-branchial index),²⁵⁴ as well as new biomarkers (high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, secretory phospholipase A2)²⁵⁵ will contribute to personalized diagnosis, risk stratification, and disease phenotyping.

Monogenic Coronary Artery Disease

AD CAD (#608320, ADCAD1) associated with mutations in MEF2A gene (*600660; first reported AD MI²⁵⁶ but later not confirmed²⁵⁷) and ADCAD2 (#610947) associated with mutations in the LRP6 gene (*603507) are not confirmed. Susceptibility genes and loci to MI (LRP8, GCLM, TNFSF4, LTA, GCLC, ESR1, OLR1, F7, PSMA6, ITGB3, MIAT, LGALS2) should be considered provisional. The expansion of investigation for individual whole risk can beneficially start from comprehensive phenotype investigation, including evaluation of comorbidities, exposures to high risk environment, disease mapping clinical monitoring, and family studies exploring both events and risk factors.

Family History of Coronary Artery Disease

A positive family history, a nonmodifiable risk factor, is the sum of the low effect of multiple genetic variants and familial environmental risk factors. Gender-related imprinting contributes to family-related risk: the paternal history of MI may simply reflect the higher prevalence of MI in males, whereas the less common maternal history of MI carries a higher risk.²⁵⁸ A gender-related parental effect also includes risk factors such as type 1 diabetes,²⁵⁹ suggesting the involvement of imprinted genes. The relative risk of MI is higher in individuals with one or more affected first-degree relatives and further increases when relatives are affected at earlier ages²⁶⁰ (Figs. 9–9 and 9–10). Studies in twins demonstrated a higher risk of coronary death after one twin died of premature CAD.²⁶¹ Twin studies also contributed to highlighting genetic factors^262,263 and dissecting genetic and environmental-related risk. Nonetheless, precise estimation of family-related risk remains difficult in clinical practice because its contribution is subject to classification errors and bias, as well as descriptive ability and recall of participants. For risk factors such as cigarette smoking, metabolites associated with smoking behaviors could provide more precise data than those obtained by counting the number of cigarettes per day or packs per year,²⁶⁴ facilitating accurate partition of components of positive family history, family-related environment, and entirely exogenous factors.

Familial environment can contribute to the risk. Dietary styles are influenced by familial lifestyles. The first quarter of an individual’s life is spent within family; thereafter, each individual may either maintain the familial lifestyle or modify his or her habits. Well-balanced diets (plant- vs meat-based diets, intake of polyunsaturated fatty acids, low salt consumption) are protective; even factors such as salt taste, which is partially under genetic control,²⁶⁵ can be regenerated²⁶⁶ and therefore be modifiable. Regular, moderate exercise is protective against acute MI. Early childhood attitude to sport influences exercise levels throughout life: monozygotic twins demonstrated long-term familial aggregation of adherence to exercise.²⁶⁷ Parental use of tobacco and reduced family cohesiveness are essential components of positive preteen attitudes toward smoking; family-based interventions can prevent children and adolescents from starting to smoke.²⁶⁸ Common infections cluster in families and institutions, and the relationship between MI and chronic infections caused by Helicobacter pylori, cytomegalovirus, Chlamydia pneumoniae, hepatitis viruses, or oral pathogens is still a matter of debate.^269,270,271 Certain infections may influence systemic inflammation and therefore contribute to atherothrombosis.²⁷²

Factors that may influence the risk of, or protect from, CAD include (1) low-dose input of different genes playing roles in known pathways with biological plausibility with respect to current knowledge on risk and events and (2) pathways without immediate biological plausibility (ie, transcription factors and increased risk of MI).²⁷² The occurrence of MI in individuals without traditional risk factors highlights the existence of powerful, still unknown mediators that play their role independently of, or in addition to, the underlying coronary ATS. Genetic risk of CAD as a whole may not coincide with the genetic risk of MI. Studies distinguishing MI series from coronary atherosclerosis series demonstrated risk loci in patients with angiographic CAD (eg, the 15q25.1 ADAMTS7 locus) but not MI, as well as risk loci shared by both CAD and MI (9q34.2 ABO locus).^273,274 Replicated studies support the role of genes partaking in coagulation or inflammatory pathways, or of chromosomal loci in which still unknown candidate genes map. In a recent meta-analysis, patients with coronary atherosclerosis who carry the high-risk genotype of the 9p21-3 allele may be more likely to have multivessel CAD²⁷⁵; at present, SNP markers in the 9p21 chromosomal locus seem to be robust GWAS signals for CAD risk.²⁷⁶ These data are not translated into current clinical practice.

Gene-Environment Interactions

Individuals who are genetically predisposed to MI (positive family history) but not exposed to acute or chronic environmental risk factors may not develop MI, and vice versa. Genetic predictors of minor risk in the overall population may predict a high risk in specific subsets of individuals as a result of gene-environment interactions, including cigarette smoking, infections, meals, and drugs. For example, the CYP2B6 allele seems to increase the risk of tobacco dependence throughout adolescence.²⁷⁷ The rs1051730 (C/T) SNP, which is a tag for multiple variants in the CHRNA5-CHRNA3-CHRNB3 gene cluster, is associated with an increased risk of death in smokers²⁷⁸ and variants in Rho-GTPase pathway genes seem to exert their effects in early-onset CAD.²⁷⁹ Recent epigenome-wide methylation studies demonstrated that DNA hypomethylation in certain genes is associated with tobacco exposure.^219,280 Specific methylation markers may show gradual reversal of methylation levels from those typical of current smokers to those have never smoked.²⁸¹ DNA methylation may also be associated with modulation of the risk related to diabetes mellitus, with TXNIP gene methylation being associated with sustained hyperglycemia levels (HbA1c ≥ 7%).²⁸²

Future Developments

The awareness of clinical and molecular genetics in multifactorial diseases is modifying models of care and introducing novel outpatient models for genetic investigation,²⁸³ including systematic genetic testing in phenotypically characterized high-risk patients (such as children with hypercholesterolemia),²⁸⁴ and is expanding information on genetic risk of CAD and conventional risk estimates to patients.²⁸⁵ Family history and deep phenotyping of patients and relatives may contribute to characterize correlations between genetic risk and overall risk, events, and outcome. New, targeted treatments are becoming available for subgroups of patients with well-characterized phenotype and genotype. These include gene-based agents, eg, mipomersen, approved in the United States for homozygous familial hypercholesterolemia; and Glybera, AAV1-LPLS447X gene therapy, conditionally approved in Europe for lipoprotein lipase deficiency²⁸⁶ in carriers of null LDLR mutations who are at increased risk, even in the setting of early diagnosis and regular lipid-lowering treatments.

The burden of known and emerging heritable cardiovascular diseases is increasing as a result of the translation of precise diagnosis of both deep phenotyping and genetic causes. The majority of these diseases were previously thought to have genetic bases, but many of them were simply included in the broad group of phenotypically similar disorders (such as CMPs, aortopathies, and lone AF, among others).

The tremendous progression of molecular genetics is now calling for a similar effort in deep phenotyping of different genetic cardiovascular diseases, with the major aim of characterizing specific disorders caused by mutations in different genes. This action includes systematic clinical family screening when patients are recognized as affected by a potential genetic disease. Genetic rules do not differ from those of other genetic diseases. However, phenotyping requires cardiologists to go back to clinics and pursue the physical examination of patients with an interdisciplinary “disease and genetically oriented” mindset. The fast rate of gene mutation and variant detection further makes it important to know the fundamentals for interpretation of genetic tests and to assess the segregation of genotype with phenotype in families. The enthusiasm supporting this effort comes from the increasing number of targeted treatments for specific diseases and from the realization that personalized care programs can be implemented for precisely diagnosed cardiovascular diseases.