Diagnostic Yield of Genetic Testing in Young Patients With Atrioventricular Block of Unknown Cause

Background The cause of atrioventricular block (AVB) remains unknown in approximately half of young patients with the diagnosis. Although variants in several genes associated with cardiac conduction diseases have been identified, the contribution of genetic variants in younger patients with AVB is unknown. Methods and Results Using the Danish Pacemaker and Implantable Cardioverter Defibrillator (ICD) Registry, we identified all patients younger than 50 years receiving a pacemaker because of AVB in Denmark in the period from January 1, 1996 to December 31, 2015. From medical records, we identified patients with unknown cause of AVB at time of pacemaker implantation. These patients were invited to a genetic screening using a panel of 102 genes associated with inherited cardiac diseases. We identified 471 living patients with AVB of unknown cause, of whom 226 (48%) accepted participation. Median age at the time of pacemaker implantation was 39 years (interquartile range, 32–45 years), and 123 (54%) were men. We found pathogenic or likely pathogenic variants in genes associated with or possibly associated with AVB in 12 patients (5%). Most variants were found in the LMNA gene (n=5). LMNA variant carriers all had a family history of either AVB and/or sudden cardiac death. Conclusions In young patients with AVB of unknown cause, we found a possible genetic cause in 1 out of 20 participating patients. Variants in the LMNA gene were most common and associated with a family history of AVB and/or sudden cardiac death, suggesting that genetic testing should be a part of the diagnostic workup in these patients to stratify risk and screen family members.

[1]  K. Nikus,et al.  Timing of pacemaker and ICD implantation in LMNA mutation carriers , 2021, Open Heart.

[2]  H. Bundgaard,et al.  Long-term outcomes in young patients with atrioventricular block of unknown aetiology , 2021, European heart journal.

[3]  K. Musunuru,et al.  Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. , 2020, Circulation. Genomic and precision medicine.

[4]  T. Laitinen,et al.  Cardiomyopathy associated with the Ala143Thr variant of the α-galactosidase A gene , 2020, Heart.

[5]  T. Mazza,et al.  Double missense mutations in cardiac myosin‐binding protein C and myopalladin genes: A case report with diffuse coronary disease, complete atrioventricular block, and progression to dilated cardiomyopathy , 2020, Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc.

[6]  H. Bundgaard,et al.  Aetiologies and temporal trends of atrioventricular block in young patients: a 20-year nationwide study , 2019, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[7]  R. Vasan,et al.  Familial Clustering of Cardiac Conduction Defects and Pacemaker Insertion. , 2019, Circulation. Arrhythmia and electrophysiology.

[8]  S. Boulé,et al.  High-degree atrioventricular block revealing hypertrophic cardiomyopathy related to a mutation in MYBPC3 gene. , 2019, Presse medicale.

[9]  P. Postema,et al.  Determination and Interpretation of the QT Interval: Comprehensive Analysis of a Large Cohort of Long QT Syndrome Patients and Controls , 2018, Circulation.

[10]  Pelin Ayyıldız,et al.  Rhythm disturbances and treatment strategies in children with congenitally corrected transposition of the great arteries , 2018, Congenital heart disease.

[11]  T. Edvardsen,et al.  Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation , 2017, European heart journal.

[12]  Hannes P. Eggertsson,et al.  Whole genome characterization of sequence diversity of 15,220 Icelanders , 2017, Scientific Data.

[13]  Sang Hyun Park,et al.  Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey , 2017, Medicine.

[14]  Steven K. Carlson,et al.  Bradyarrhythmias in Congenital Heart Disease. , 2017, Cardiac electrophysiology clinics.

[15]  Keith Nykamp,et al.  Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria , 2017, Genetics in Medicine.

[16]  Y. Pinto,et al.  Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy , 2017, European journal of heart failure.

[17]  W. Chantratita,et al.  Exome Sequencing Identifies Compound Heterozygous Mutations in SCN5A Associated with Congenital Complete Heart Block in the Thai Population , 2016, Disease markers.

[18]  P. Taimen,et al.  Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy , 2016, Journal of Cell Science.

[19]  N. Combes,et al.  Congenital and childhood atrioventricular blocks: pathophysiology and contemporary management , 2016, European Journal of Pediatrics.

[20]  Andrea Mazzanti,et al.  2015 ESC Guidelines for the Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. , 2016, Revista espanola de cardiologia.

[21]  A. Bucchi,et al.  The genetic basis for inherited forms of sinoatrial dysfunction and atrioventricular node dysfunction , 2015, Journal of Interventional Cardiac Electrophysiology.

[22]  J. Healey,et al.  Atrioventricular Block as the Initial Manifestation of Cardiac Sarcoidosis in Middle‐Aged Adults , 2014, Journal of cardiovascular electrophysiology.

[23]  P. Laforêt,et al.  Atrio-ventricular block requiring pacemaker in patients with late onset Pompe disease , 2014, Neuromuscular Disorders.

[24]  J. Nielsen,et al.  ESC Guidelines on cardiac pacing and cardiac resynchronization therapy , 2014 .

[25]  Lluís Mont,et al.  2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. , 2014, Revista espanola de cardiologia.

[26]  Y. Pinto,et al.  The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins. , 2013, Experimental cell research.

[27]  W. Groh.  Arrhythmias in the muscular dystrophies. , 2012, Heart rhythm.

[28]  Mugen Liu,et al.  Identification of a new lamin A/C mutation in a chinese family affected with atrioventricular block as the prominent phenotype , 2010, Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban.

[29]  J. Joglar,et al.  A novel mutation in LAMIN A/C is associated with isolated early-onset atrial fibrillation and progressive atrioventricular block followed by cardiomyopathy and sudden cardiac death. , 2009, Heart rhythm.

[30]  Robert G. Weiss,et al.  ECG Quantification of Myocardial Scar in Cardiomyopathy Patients With or Without Conduction Defects: Correlation With Cardiac Magnetic Resonance and Arrhythmogenesis , 2008, Circulation. Arrhythmia and electrophysiology.

[31]  Luying Peng,et al.  Human KCNQ1 S140G mutation is associated with atrioventricular blocks. , 2007, Heart rhythm.

[32]  S. Ellard,et al.  The laminopathies: a clinical review , 2006, Clinical genetics.

[33]  R. Hui,et al.  Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect. , 2006, Biochemical and biophysical research communications.

[34]  H. Crijns,et al.  Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? , 2004, Journal of Molecular Medicine.

[35]  M. Komajda,et al.  Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations , 2003, Journal of medical genetics.