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Introduction

Cardiac conduction disease (CCD) is very common in clinical practice. Its description dates back to more than a century ago. Although the co-occurrence of fainting episodes and severe bradycardia was reported by Morgagni in the eighteenth century and again later by Stokes and Adams (to whom the term Stokes-Adams attacks was dedicated) [21, 37], the first documentation of atrioventricular block (AVB) on surface electrocardiography (ECG) was achieved later [75]. Familial CCD has been first described in 1901 by Morquio, and by many others thereafter [33, 45, 46, 52].

Reflecting its numerous etiologies and electrical manifestations, the definition of CCD is highly variable. We here define it as any persistent defect in the formation or propagation of the cardiac impulse at any level of the specialized cardiac electrical system in the absence of drug or metabolic disturbance known to affect cardiac conduction. Unlike most cardiovascular conditions discussed in this book, CCD is primarily caused by nongenetic etiologies (Table 16.1). In many cases, CCD is secondary to structural heart disease (e.g., ischemic heart disease, cardiomyopathy), to a cardiac intervention (e.g., aortic valve replacement, arrhythmia ablation) or to an autoimmune process (e.g., neonatal lupus syndrome). CCD can also be primary, most often in the context of senile degeneration of the conduction system in an elderly patient. Primary CCD in a young patient should raise the suspicion for an inherited etiology, especially if there is a positive family history. The mechanism of CCD is either functional (decreased depolarizing currents or impaired cellular coupling) and/or associated with premature conduction system degeneration (referred to as Lenègre’s disease). This chapter is focused on primary CCD in the young, which could have an inherited etiology. We review the subject in a clinically oriented manner, in a similar fashion as other chapters. A general discussion on the clinical evaluation and management of suspected hereditary CCD will be followed by a review of the molecular genetics of the disease (section “Molecular Genetics”) highlighting gene-specific aspects.

Table 16.1 Etiologies of CCD
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Clinical Presentation

Primary CCD is a progressive disease with variable age of onset and clinical course. During early stages, patients are generally asymptomatic, and ECG abnormalities are detected incidentally or during family screening. With the progression of disease, symptoms occur either because of severe bradycardia or chronotropic incompetence (incapacity to increase heart rate during exercise). In the former, patients may present with pre-syncope or syncope occurring during periods of ventricular asystole (typically >4 s), due to sinus pauses or high degrees of AVB. In the latter, patients could present with exercise intolerance and/or dyspnea. Rarely, patients can be symptomatic in the absence of severe bradycardia and chronotropic incompetence. This may occur because of hemodynamic consequences of electrical dyssynchrony (e.g., excessive PR prolongation causing atrioventricular (AV) dyssynchrony) or due to reentrant arrhythmia secondary to excessively slowed conduction (e.g., bundle-branch reentrant ventricular tachycardia).

Hereditary forms of CCD can be associated with other cardiac electrical or structural diseases as well as neurological disease (Table 16.2). As such, the first manifestation of disease might not be related to CCD but to the associated disease. For instance, patients with loss of function mutations in SCN5A can have both Brugada syndrome (BS) and CCD. In such cases, the first manifestation of disease can be ventricular arrhythmias in the context of BS. Patients with mutations in NKX2-5 also present with atrial septal defects (ASDs), while patients with LMNA mutation typically develop CCD in association with dilated cardiomyopathy (DCM) in a later stage of disease development. Other genotype-phenotype correlations are summarized in Table 16.2 and further discussed below. A detailed review of symptoms, physical examination, and cardiac imaging is thus crucial in establishing a correct diagnosis and guide molecular genetic testing.

Table 16.2 Clinical characteristics of the major subtypes of hereditary CCD
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Systematic longitudinal data on the course and natural history of hereditary CCD are limited. When available, such data will be discussed below along with the specific genetic defects (section “Molecular Genetics”). By contrast, the clinical course and prognosis of conduction defects in the general population without known structural heart disease has been abundantly studied. For instance, unexplained sinus bradycardia (<50 beats/min) in healthy volunteers is not associated with adverse events during a mean follow-up of 5.4 years [74]. In a Finnish populational study of 10,685 individuals aged 30–59 years old and followed up for 30 ± 11 years, isolated first-degree AVB (2.1 % of patients) was not associated with an increased risk of adverse events [6]. Mobitz type I second-degree AVB in individuals without underlying heart disease, as often seen in athletes due to increased vagal tone, is often caused by block in the atrioventricular node and also has a benign prognosis [72]. By contrast, Mobitz type II second-degree AVB is caused by conduction block below the AV node and is associated with a bad prognosis, with a high risk of progression to complete AVB, syncope, and sudden cardiac death (SCD) [25]. The association of right bundle-branch block (RBBB) with mortality in the general population is controversial, with a recent meta-analysis showing an increased risk of mortality during follow-up (HR 1.17; 95 % confidence interval (CI): 1.03–1.33) [86]. The prognosis of left bundle-branch block (LBBB) in asymptomatic healthy individuals appears to be age-dependent. Earlier large cohort studies including patients with a mean age below 55 and a mean follow-up less than 10 years do not detect an increased adverse event rate associated with LBBB [29, 61]. By contrast, more recent studies including older patients and longer follow-up show a significant increase in high-degree AVB, cardiovascular, as well as total mortality [7, 28, 87]. Taken together, these data suggest that conduction defects in the young asymptomatic patient have a good prognosis, with the exception of Mobitz II second-degree AVB. Whether these data can be extrapolated to hereditary CCD is debatable. Since the mechanism of hereditary CCD is in part an accelerated degeneration of the conduction system, conduction defects in these patients likely occur at a higher rate than in an unselected CCD population.

Diagnosis and Differential Diagnosis

The clinical diagnosis of CCD requires the presence of a conduction abnormality on the ECG, at any single or multiple levels (Fig. 16.1). Secondary causes of CCD should be excluded (Table 16.1). An echocardiogram is indicated in all cases to assess the presence of structural heart disease, either causing or associated with CCD. Other diagnostic tests can be performed depending on patient’s age, comorbidities, and clinical findings. Accumulating evidence from independent groups suggests that cardiac sarcoidosis and giant-cell myocarditis are common causes of unexplained high-degree AVB in young patients (<55–60 years) [41, 53]. In such patients, advanced cardiac imaging with cardiac magnetic resonance (CMR) or fluorodeoxyglucose (18FDG) cardiac positron emission tomography should be considered in the diagnostic strategy. In endemic regions, Lyme disease, an infectious disease caused by the spirochete Borrelia burgdorferi should also be suspected in young patients with unexplained AVB [70]. In the presence of a clinical presentation compatible with the disease, the diagnosis is established by serologic testing. It is important to recognize this etiology in order to start an appropriate antibiotic treatment. Because AVB is most often reversible, permanent pacemaker placement is most often unnecessary.

Fig. 16.1
figure 1

(a) ECG obtained from a 50-year-old female with mild dilated cardiomyopathy (left ventricular ejection fraction, 52 %) and a truncating mutation in LMNA (Q410X) mutation. Note the low-voltage P-wave, prolonged PR interval, and narrow QRS, typical for LMNA disease. (b) ECG obtained from a 63-year-old female with structurally normal heart and a truncating mutation in SCN5A (R222X). Note the prolonged PR and QRS intervals and left-axis deviation, typical for SCN5A loss of function mutations

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A three-generation family history is recommended when evaluating a young patient with an unexplained cardiac conduction defect. Family history taking is detailed in Chap. 2. In the context of CCD, one should specifically assess for the presence of family history of CCD, SCD, arrhythmia, pacemaker or defibrillator implantation, heart failure or cardiomyopathy, cardiac transplantation, congenital heart disease, as well as neuromuscular disease. When assessing the inheritance pattern, one should note that CCD often accompanies many acquired diseases. For instance, ischemic or valvular heart diseases are common causes of CCD. Age is also an important factor in interpreting family history. The prevalence of CCD greatly increases with age. In a prospective cohort study of randomly selected 855 males born in 1913 [27], the prevalence of bundle-branch block increased from 1 % at the age of 50 to 17 % at 80 years old. Likewise, populational studies from the United States and Australia estimate the prevalence of permanent pacemaker therapy to be less than 0.5 % in patients below 65 years old but higher than 2 % in patients over 75 years old [16, 65]. This age-dependent prevalence is important to keep in mind when assessing the etiology of CCD in family members: In young patients, CCD is rare and more likely to be inherited, while CCD in older patients is common and more likely to be caused by senile degeneration of the conduction system. In sum, a detailed clinical review of family members with suspected CCD, including age at onset and comorbidities, is important to understand the presence and pattern of heritability and identify phenocopies.

Clinical Therapy and Follow-up

The management of patients with CCD is aimed at alleviating symptoms and preventing SCD. No drug therapy is yet available. Pacemaker implantation is indicated in patients with symptomatic bradycardia as well as those at a high risk of complete AVB and SCD. Clinical guidelines on cardiac pacing are periodically updated and published [17]. With the exception of a few locus- and disease-specific management differences (e.g., LMNA mutations, muscular dystrophies; discussed below), patients with suspected or established hereditary CCD are treated similarly as patients with other etiologies of CCD.

In the following situations, pacemaker implantation is recommended (Class I indication):

  • Sinus node dysfunction with symptoms clearly attributed to bradycardia

  • Third-degree or Mobitz II second-degree AVB, irrespective of symptoms

  • Syncope with bundle-branch block and demonstration of conduction impairment below the AV node during an invasive electrophysiological study

  • Alternating bundle-branch block (e.g., RBBB and LBBB), irrespective of symptoms

In the following situations, pacemaker implantation should be considered (Class IIa indication):

  • Mobitz I second-degree AVB, with symptoms or invasive study showing a block below the AV node

  • Syncope and demonstration of asymptomatic pauses for >6 s

Because of the progressive nature of the disease, a recent expert consensus statement on inherited arrhythmia syndromes also suggests that pacemaker implantation be considered (Class IIa) in the presence of bifascicular block with or without first-degree AVB [58].

Patients with manifest CCD as well as carriers of a pathogenic loss of function mutation in SCN5A should also avoid the use of medication with conduction-slowing properties, such as those listed in http://www.brugadadrugs.org [57].

Since the disease is progressive, patients with CCD should be periodically assessed with ECG and review of symptoms. Longer ECG recordings such as Holter monitoring and loop recording should be considered in symptomatic patients without ECG criteria for pacemaker implantation, to detect intermittent deterioration of the conduction abnormality. Patients reporting exercise intolerance should undergo exercise testing to detect chronotropic incompetence or exercise-induced AVB. Echocardiography should also be repeated in select patients, periodically in LMNA, DES, and SCN5A mutation carriers and whenever there is clinical suspicion of heart failure. The frequency of follow-up should be individualized, taking into account the severity of conduction anomalies, the rate of disease progression, the presence of symptoms, and the patient’s age. Patients with muscular dystrophy and CCD should be monitored more closely. Patients should be advised to consult rapidly if they have a syncopal event, to assess the need for an urgent pacemaker implantation.

Molecular Diagnostics

Genetic testing should be considered in patients with primary CCD developing at a young age (<50 years old) with or without cardiomyopathy or congenital heart disease, especially in the presence of a positive family history [2]. The optimal diagnostic strategy remains unclear. As for other conditions, one should balance the desires for getting a higher yield yet avoiding the detection of variants of unknown significance. In patients with isolated CCD, sequencing of TRPM4 and SCN5A is desirable. For those with associated DCM, sequencing of LMNA, DES, and SCN5A should be undertaken, while patients with CCD associated with congenital heart defects such as ASDs can be screened for mutations in NKX2-5 and TBX5. Mutations in other genes have been identified in few families or isolated cases with CCD, with some supportive functional data. These genes often appear on next-generation sequencing (NGS) “arrhythmia” or “cardiac” panels. Data from the Netherlands suggest the yield of genetic testing in CCD (mostly limited to SCN5A sequencing) to be approximately 30 %, with a single recurrent SCN5A mutation (c.2582_2583delTT) accounting for most of the cases [39]. The yield of targeted genetic testing in large diverse populations and the added value of NGS remain to be explored.

Molecular Genetics

SCN5A

Mutations in SCN5A causing CCD were first identified by Schott [62]. The authors reported a large French family with autosomal dominant CCD presenting with first-degree AVB, LBBB, RBBB, or complete AVB requiring pacemaker implantation, in the absence of structural heart disease. Follow-up of the family showed a progressive disease. Using a targeted-linkage approach, the authors demonstrated a strong linkage to the 3p21 locus, which harbors SCN5A. Sequencing revealed a splice-site variant predicting skipping of exon 22. The authors also performed sequencing of SCN5A in an independent Dutch nuclear family with asymptomatic first-degree AVB, RBBB, and/or nonspecific intraventricular conduction delay and identified a frameshift variant predicting a premature stop codon and cosegregating with the phenotype. In sum, this study was the first to link CCD with SCN5A, which was earlier identified as a disease gene in long QT syndrome type 3 (LQT3) [83] and BS [20]. Similar to BS, SCN5A mutations causing CCD result in loss of function of Nav1.5, the major cardiac sodium channel responsible of cardiomyocyte depolarization. It is thus not uncommon for loss-of-function mutations to result in a mixed phenotype of BS and CCD, either in the same patient or in family members carrying the same variant. By contrast, LQT3 is caused by gain of function SCN5A mutations, which result in impaired inactivation of Nav1.5 with increased late sodium current. Interestingly, mutations resulting in both a decrease in peak sodium current (loss of function) and increase in late current (gain of function) have been identified in families with CCD, BS, and LQT3 [59]. The 1795insD mutation is the best characterized example of such an overlap syndrome [56]. SCN5A mutations have also been observed in families with sinus node dysfunction, atrial fibrillation, as well as DCM, emphasizing the high heterogeneity of phenotypes associated with SCN5A [79]. Highlighting the important role of SCN5A and its product Nav1.5 in normal cardiac electrical function, common variants in the SCN5A-SCN10A locus have been associated with PR, QRS, and QT intervals as well as BS and ST-T voltages in multiple genome-wide association studies (GWAS) [4, 11, 40, 55, 66, 81].

Clinically, CCD associated with SCN5A mutations initially presents with a prolonged PR interval, wide QRS as well as left-axis deviation (Fig. 16.1b), which could progress to high-degree AVB. In addition to the general CCD management described in section “Clinical Therapy and Follow-up”, patients with a pathogenic mutation in SCN5A should be counseled to avoid drugs with sodium-channel-blocking effects and should suppress fever, a potential trigger of arrhythmic events. Because of the possible overlap with other syndromes causing ventricular tachyarrhythmia, one should be attentive to investigate syncopal events appropriately, as these may sometimes be caused by malignant ventricular arrhythmia. While a standard pacemaker is usually the treatment of choice (when indicated, see above), some patients may benefit from an implantable cardioverter defibrillator (ICD), especially in overlap syndromes.

TRPM4

In 2009, mutations in TRPM4 were identified as a cause of CCD [42]. In fact, the story behind this discovery dates back to the 1960s, when Combrink et al. [21] and later Steenkamp et al. [69] described large South African families with autosomal dominant CCD manifesting as RBBB, fascicular blocks, and SCD. Later, a large Lebanese family with a similar phenotype was reported [71]. In 1995, linkage analysis in both the South African and Lebanese families mapped the CCD phenotype to chromosome 19q13.3, which includes TRPM4 [18, 23]. Sequencing of TRPM4 identified two different missense mutations in these families, cosegregating with the CCD phenotype [42, 43]. Mutations were also identified in an additional large French family as well as smaller families and sporadic cases with CCD [22, 43, 68]. Based on recent data from relatively small cohorts without systematic cosegregation analysis, the estimated yield of TRPM4 testing in progressive CCD is about 15 % [22, 68]. Of note, the classic phenotype of TRPM4-related CCD is that of RBBB with or without fascicular block, which progresses to complete AVB, but rarely isolated LBBB.

TRPM4 encodes a Ca2+-activated nonselective cation channel predominantly expressed in Purkinje fibers. The mechanism of TRPM4-related CCD is attenuated deSUMOylation of the protein, which results in decreased endocytosis, thus increasing channel density at the cell surface [42]. This increased cation channel density is thought to result in membrane depolarization, thus reducing the availability of Nav1.5, necessary for fast conduction in the specialized cardiac conduction system [1].

LMNA

Mutations in LMNA are associated with a wide spectrum of diseases, known as laminopathies. These include Hutchinson-Gilford progeria, autosomal recessive Charcot-Marie-Tooth, Emery-Dreifuss muscular dystrophy (EDMD), as well as DCM preceded by or accompanied with marked CCD. LMNA-related cardiomyopathy is a progressive disease which initially presents with CCD, typically sinus bradycardia, low-voltage P-waves, first-degree AVB, and initially a normal QRS (Fig. 16.1a). The disease is often accompanied by arrhythmia starting at an early stage (premature atrial complexes, atrial tachycardia or fibrillation, premature ventricular complexes or VT). With disease progression, the patient could present with complete AVB, malignant ventricular arrhythmia or SCD, and eventually DCM with heart failure or embolic stroke. Family data suggest that CCD typically precedes DCM by a median time interval of 7 years [19]. Patients with CCD and an LMNA mutation have a high risk of developing malignant ventricular tachyarrhythmia, even if left ventricular systolic function is preserved [3, 38]. In patients with an indication for pacemaker therapy and an LMNA mutation, ICD implantation should thus be considered [58], especially in the presence of additional risk factors such as male sex, nonsustained VT, left ventricular ejection fraction <45 %, and the presence of a non-missense mutation [76].

When no mutation is detected in LMNA by sequencing in a patient with a typical presentation (CCD, DCM, arrhythmia, and family history), one should consider testing for structural variants, such as a large deletion, using appropriate techniques (e.g., multiplex ligation-dependent probe amplification). Such an approach has been proven useful in some cases [36, 48, 78].

CCD Associated with Congenital Heart Defects: NKX2-5 and TBX5

In 1998, Schott identified one missense and two nonsense variants in NKX2-5 in four families affected with an autosomal dominant form of congenital heart defects, mostly (27 of 33 cases) secundum ASDs but also a few with other defects with or without ASD [63]. All affected individuals had CCD manifesting as various degrees of AVB. Invasive electrophysiological studies performed in three patients revealed that the site of conduction delay was the AV node, and patients who were later followed up show progressive CCD. NKX2-5 encodes a transcription factor involved in cardiac morphogenesis, specifically in septation during development and is also important for normal function of the AV node in postnatal life. Other groups also reported mutations in NKX2-5 in smaller families with a similar phenotype, reproducing the original findings [67].

Holt-Oram syndrome (HOS) is an autosomal dominant disease affecting the heart and hand (heart and hand syndrome) and is caused by mutations in the transcription factor TBX5 in >70 % of cases [9, 49]. Virtually all affected individuals have skeletal anomalies involving the radius, carpal, or hand bones, sometimes only seen on radiography. Most patients also have a congenital heart defect, typically a secundum ASD or VSD, but more severe lesions have been reported. Patients with the syndrome are also at risk for severe progressive CCD requiring pacemaker implantation, regardless of the presence of a structural defect. The exact prevalence of CCD in HOS has not been reported. Likewise, the prevalence of pathogenic TBX5 mutations in suspected hereditary CCD is unknown. Both missense and truncating TBX5 variants have been associated with HOS. The mutation type and the location of missense variants have been suggested as predicting the phenotype [10]. In the presence of a typical HOS and absence of mutation using sequencing, one should also consider testing for large deletions, which have been previously reported [15]. TBX5 is critical for normal cardiac development in prenatal life, while its control of SCN5A expression makes it important in regulating cardiac conduction in postnatal life [5]. In addition to its involvement in HOS, GWAS identified common variations in the TBX5 locus associated with both PR and QRS durations, again highlighting its role in normal cardiac conduction [24, 40, 66].

CCD Associated with Muscular Dystrophies: An Overview

Muscular dystrophies are a group of clinically and genetically heterogeneous inherited skeletal muscle diseases that often also affect the heart [34]. The prevalence, type, and severity of cardiac involvement depend on the specific muscular dystrophy. In the X-linked recessive Duchenne and Becker dystrophies caused by mutations in dystrophin (DMD), DCM is the predominant cardiac phenotype and CCD is infrequent. By contrast, the autosomal dominant myotonic dystrophies caused by repeat expansions in DMPK (type 1) or CNBP (type 2), CCD is very common and progressive while DCM is uncommon. In myotonic dystrophy type I (Steinert’s disease), the majority of patients develop CCD. When CCD is severe (defined as nonsinus rhythm, PR >240 ms, QRS >120 ms, or second- or third-degree AVB), it is associated with an increased risk of SCD [35]. Interestingly, the number of CTG repeats in DMPK and the severity of the muscular phenotype are predictors of severe CCD. Because SCD is responsible for 30 % of mortality and that CCD is thought to play a major role in the mechanism of SCD, the threshold for pacemaker implantation should be low in patients affected with this disease. While the presence of second- or third-degree AVB is a clear indication for pacemaker implantation, the optimal approach for risk stratification and prophylactic device implantation in other patients remains unclear. Some experts suggest the use of an invasive electrophysiological study. A large nonrandomized study showed that an invasive electrophysiological study-guided device implant strategy was associated with increased survival, when compared to a conservative noninvasive strategy, after adjusting for baseline differences or matching using propensity scores [82]. Because of a risk of ventricular arrhythmia-mediated SCD, ICD implantation should also be considered instead of a standard pacemaker [12]. EDMD is a rare disease inherited as either X-linked recessive (caused by mutations in EMD or FHL1) or autosomal dominant or recessive (mutations in LMNA). EDMD is associated with CCD presenting with sinus bradycardia, atrial standstill, and AVB. Patients are also at risk of DCM and atrial arrhythmias with cardio-embolic stroke [14]. Both autosomal dominant and X-linked recessive EDMD forms are at risk, but LMNA mutation carriers are believed to be at a higher risk to have a cardiac involvement [13]. LMNA mutations can also cause autosomal dominant limb girdle muscular dystrophy (LGMD) type IB with a high prevalence of cardiac involvement (CCD and DCM). Other autosomal dominant and autosomal recessive subtypes of LGMD can be associated with DCM at various degrees but rarely with CCD. Other types of muscular dystrophies are rarely seen in the context of CCD or DCM.

Myofibrillar myopathy is another genetically heterogeneous neuromuscular disease associated with CCD with or without DCM. Its most common form observed in cardiogenetics is the autosomal dominant desmin-related myopathy. The latter is caused by mutation in DES and is characterized by isolated cardiac involvement (25 %), isolated neurological involvement (25 %), or both (50 %) [77]. Cardiac disease consists of cardiomyopathy (mainly DCM), CCD, supraventricular arrhythmias, as well as ventricular arrhythmias including a few cases of SCD despite a pacemaker. Considering the potential risk of SCD from ventricular arrhythmias, some clinicians suggest the use of an ICD in DES mutation carriers with a pacemaker indication [77]. Mitochondrial disease caused by mitochondrial DNA deletion can also present with both a neuromuscular defect and CCD with or without cardiomyopathy. The Kearns-Sayre syndrome is the classic example, where rapidly progressive AVB is observed.

Management of patients with neuromuscular disease and CCD can be challenging given the limited available literature and the associated muscular morbidity. Given the increased risk of SCD in many of these diseases, clinical practice guidelines suggest a more aggressive approach than with other CCD patients. For instance, permanent pacemaker implantation may be considered for myotonic dystrophy and limb-girdle muscular dystrophy, with any degree of AV block (including first-degree AV block) or bifascicular block, with or without symptoms [26]. Such an aggressive approach based on little clinical data does not make a consensus among experts [17].

Other CCD Genes

Loss-of-function mutations in HCN4, which encodes the major pacemaker channel protein in humans, have been identified in patients and families with sinus node dysfunction, sometimes in association with paroxysmal atrial fibrillation [50, 64]. The severity of the phenotype is highly variable and sometimes benign with isolated asymptomatic sinus bradycardia in a whole family [54]. Recently, loss-of-function mutations were identified in four families with sinus bradycardia in combination with left ventricular noncompaction cardiomyopathy [51] and mild aortic dilatation [80]. Of interest, a gain-of-function mutation in HCN4 was identified in a familial form of inappropriate sinus tachycardia [8].

The cardiac voltage-gated sodium channel (Nav1.5) is part of a protein complex composed of the α-subunit (encoded by SCN5A), as well as β-subunits (e.g., SCN1B) and ancillary proteins. Following the association of SCN5A with CCD and BS, a candidate gene-sequencing study identified mutations in SCN1B in three small pedigrees affected by CCD with or without BS [84]. The investigators performed functional studies showing that coexpression of SCN5A with the mutant SCN1B resulted in a decreased sodium current as compared to coexpression of both wild-type proteins. Although these functional data are supportive, the lack of robust human genetic data (three small pedigrees and lack of convincing validation studies) makes one question the role of SCN1B in CCD.

The fast propagation of the electrical impulse in the His-Purkinje system depends on the availability of Nav1.5 and also high-conductance gap junctional channels. In a 6-year-old boy with CCD (LBBB and second-degree AVB) who later died suddenly, Makita et al. [47] identified a missense variant in GJA5, which encodes the high-conductance gap junctional channel subunit connexin40. The variant was also present in his mother with documented CCD (LBBB) who later had a SCD, as well as in his 4-year-old sister with a QRS duration at the upper limit of normal. Expression of the mutant proteins showed a reduction in junctional conductance compared to wild-type connexin40. Somatic GJA5 mutations in left atrial DNA have also been previously identified in patients with atrial fibrillation [31], although this finding was not reproduced in a larger cohort [60] (see Chap. 15 for discussion).

Recently, using linkage analysis and whole-exome sequencing, two groups identified missense variants in TNNI3K in families with supraventricular tachyarrhythmia and CCD, sometimes associated with DCM [73, 85]. TNNI3K encodes for the Troponin I-interacting kinase, a cardiac-specific kinase that was previously implicated in atrioventricular conduction in mice [44]. The pathophysiological mechanism implicating TNNI3K in arrhythmogenesis is an area of active investigation.

In 2001, Gollob identified missense mutations in PRKAG2 in families with CCD and ventricular preexcitation with or without cardiac hypertrophy [30, 32]. Multiple families with mutations in PRKAG2 and an identical phenotype have been identified since then. Sequencing of this gene should be performed in the presence of CCD in association with ventricular preexcitation and/or cardiac hypertrophy. PRKAG2 encodes the gamma2 regulatory subunit of AMP-activated protein kinase, which is part of the AMP-activated protein kinase complex involved in cardiomyocyte metabolism and energetics.

Family Screening

Given the limited long-term data available on familial CCD, it is difficult to recommend a detailed family screening and follow-up algorithm. Instead, the clinician should adapt the follow-up plan to each patient and family. Below are some points for guidance depending on whether a pathogenic variant is identified and whether the disease is familial or sporadic.

When a pathogenic mutation is identified in the proband, cascade screening using mutation analysis in family members is recommended [2]. Mutation carriers should have a complete baseline cardiological evaluation, consisting of a review of symptoms, physical evaluation, ECG, and echocardiography. Exercise testing, Holter monitoring, or loop recoding are suggested if the patient reports any intermittent symptom. Given the progressive nature of the disease, mutation carriers need to be periodically evaluated (e.g., every 1–3 years) depending on age and the extent of ECG abnormalities, if present. Follow-up evaluation should include a review of symptoms and ECG. For patients with LMNA mutations, repeating the echocardiogram every 1–2 years is suggested. Patients should be advised to seek urgent medical attention if they present a syncopal event. Family members that do not carry the mutation can be reassured, unless the pathogenicity of the variant is questionable. A baseline ECG is encouraged, while a more extensive evaluation should be performed if symptoms develop.

In genetically elusive unexplained CCD in a young patient without a clear familial disease, a baseline ECG should be performed in first-degree relatives. If the proband also has structural heart disease, an echocardiogram should also be performed in first-degree relatives. If the baseline evaluation is normal, the patient can be discharged from cardiological care and instructed to consult if symptoms develop (e.g., pre-syncope, syncope, exercise intolerance). If the baseline evaluation is abnormal, the patient should be treated accordingly and periodically followed up.

In genetically elusive CCD with a clear familial disease, advanced genetic testing (e.g., whole-exome sequencing, large-sequencing gene panel, and targeted deletion assays) with appropriate cosegregation analysis should be considered, recognizing that the yield is likely to be low. Clinical screening of first-degree relatives should be performed as above. However, if the baseline evaluation is normal, it is probably prudent to follow-up the patients periodically for a long term, unless the disease onset in affected family members is at a young age.

Summary and Take-Home Messages

  • Cardiac conduction disease (CCD) is a clinically heterogeneous disorder involving genetic and nongenetic etiologies.

  • A genetic etiology and genetic testing should be considered in the presence of a family history of CCD, cardiomyopathy, or congenital heart disease as well as in young patients (<50 years old) with unexplained severe sporadic CCD.

  • Isolated CCD can be caused by mutations in SCN5A or TRPM4.

  • CCD in association with dilated cardiomyopathy (DCM) can be caused by LMNA and DES mutations. Patients with such mutations and severe CCD are also at risk of ventricular arrhythmia. Implantable cardioverter defibrillator (ICD) therapy should be considered in such cases.

  • CCD in association with congenital heart disease can be caused by mutations in NKX2-5 and TBX5. The latter is invariably associated with upper limb skeletal anomalies (Holt-Oram syndrome).

  • CCD in association with ventricular preexcitation or unexplained cardiac hypertrophy is suggestive for mutations in PRKAG2.

  • CCD can accompany some muscular dystrophies (e.g., myotonic dystrophy, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type IB). In these cases, aggressive therapy with a pacemaker or ICD can be considered in early stages.

  • Device therapy is the only available treatment for hereditary CCD. The decision to implant a device usually follows the same principles as with other causes of CCD, with the exceptions mentioned above.

  • Family screening with genetic testing and/or phenotypic testing is recommended in established or suspected hereditary CCD.