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Kusumoto et al 2018 Bradycardia Clinical Practice Guidelines

Circulation. 2019;140:e382–e482. DOI: 10.1161/CIR.0000000000000628 August 20, 2019 e401 CLINICAL STATEMENTS AND GUIDELINES

diagnosis can be useful.S4.2.5-1–S4.2.5-5 For example, thyroid function tests in the patient with bradycardia attributable to suspected hypothyroidism or Lyme titer to identify acute Lyme carditis in a young person who develops atrioventricular block in an endemic area.S4.2.5-3,S4.2.5-5 However, there have been no studies that have systematically evaluated the additional value of laboratory testing in patients who present primarily with bradycardia. 4.2.6. Genetic Testing in Patients With Documented or Suspected Bradycardia or Conduction Disorders

Recommendations for Genetic Testing in Documented or Suspected Bradycardia or Conduction Disorders

COR LOE Recommendations

I C-EO 1.  In patients in whom a conduction disordercausative mutation has been identified, genetic counseling and mutation-specific genetic testing of first-degree relatives is recommended to identify similarly affected individuals.

IIb C-EO 2.  In patients with inherited conduction disease, genetic counseling and targeted testing may be considered to facilitate cascade screening of relatives as part of the diagnostic evaluation.

Synopsis

Although most sinus node disorders and conduction disturbances in adults are attributable to increased vagal tone or acquired disease, genetic mutations may also contribute.S4.2.6-1–S4.2.6-4 Although familial disorders of conduction abnormalities and sinus node function are rare, a growing number of genetic mutations have been linked to a range of abnormalities that may present as isolated SND or conduction disease, or in association with cardiomyopathy, congenital cardiac anomalies, noncardiac developmental disorders, skeletal muscular disorders, or tachyarrhythmias.S4.2.6-5 The implicated genes code for ion channels and their regulatory factors, nuclear envelope proteins, membrane adaptor protein, transcription factors, calcium handling proteins of the sarcoplasmic reticulum, gap junctions, cardiac hormones, and sarcomeric proteins.S4.2.6-1

Recommendation-Specific Supportive Text

1.	 An international consensus panel has endorsed mutation-specific genetic testing for “family members and appropriate relatives” after the identification of a progressive cardiac conduction disease-causative mutation in an index case. Although the consensus document does not explicitly define “family members and appropriate relatives,” one can infer this to mean first-degree relatives (with or without evidence of conduction disease) and more remote relatives with suspicious clinical characteristics for conduction disease. Such testing can be deferred in asymptomatic children because of the age-dependent nature of progressive conduction disease and incomplete penetrance.S4.2.6-5 Asymptomatic family members who carry the conduction disease-associated mutation and those first-degree relatives of an affected proband who have not undergone mutation-specific genetic testing should be followed regularly for signs of evolving conduction disease, cardiomyopathy or tachyarrhythmia. Before mutation-specific testing, genetic counseling is essential to determine whether to proceed in an individual case. 2.	 The most common identifiable gene responsible for inherited conduction disease (the SCN5A gene encoding the cardiac sodium channel alpha subunit) accounts for only 5% of progressive conduction disease cases.S4.2.6-5 All other identified genes, in aggregate, account for a substantially smaller proportion. Mutations in the cardiac pacemaker channel gene HCN4 have been implicated in idiopathic SND.S4.2.6-6,S4.2.6-7 Nonetheless, most SND is physiologic or acquired, and genetic testing is not routinely indicated.S4.2.6-5

3.	 Citing undefined diagnostic yield and “signalto-noise” ratio for genetic testing in progressive cardiac conduction disease, as well as uncertain rates of rare variants of uncertain significance in control subjects, an international consensus document suggests that the diagnostic, prognostic and therapeutic value of genetic testing is limited in evaluating an index case.S4.2.6-5 The writing committee did not endorse routine genetic testing in patients with SND or conduction disease. Based primarily on expert opinion, the writing committee suggested that genetic testing may still be considered as part of the diagnostic evaluation for select patients with either isolated conduction disease or conduction disease with concomitant congenital heart disease, especially when there is a positive family history of conduction disease.

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