Heritability of Conduction Disturbances in the Pacemaker Clinic

Hillel Steiner ^1,3 Patrícia B. S. Celestino-Soper ² Anisiia Doytchinova ³ Ty C. Lynnes ² William J. Groh ³ John M, Miller ³ Peng-Sheng Chen ³ Matteo Vatta ²

¹Cardiovascular Medicine, The Baruch Padeh Medical Center
²Department of Medical and Molecular Genetics, Indiana University School of Medicine
³Krannert Institute of Cardiology, Indiana University School of Medicine

Introduction: The etiology of conduction disturbances necessitating pacemaker implantation is often unknown. We performed genetic sequencing of patients with pacemakers to detect pathogenic mutations.

Methods: Patients presenting to the pacemaker clinic of the Krannert Institute of Cardiology were requested to participate. Clinical characteristics including past medical history, indication for pacing and pacing history and a family tree of other relatives with pacemakers was obtained by chart review and validated by a follow up phone call.

Next generation sequencing was done using a custom panel targeting the coding sequence and neighboring splice sites for 246 genes with proven involvement in cardiac pathogenicity. The identified sequence variants were analyzed for clinical relevance by stringent standards.

Results: Of 112 patients screened, 24 had a first degree relative with an implanted pacemaker. Of these, 9 without structural heart disease or an identifiable secondary cause for conduction disturbances were selected for next generation sequencing. In four (44.4%), we identified heterozygous deleterious variants previously reported in autosomal dominant cardiac diseases including cardiac conduction defects such as the LDB3 (c.349G>A; p.D117N) and theTRPM4 (c.2531G>A; p.G844D) variants, identified in one patient. This TRPM4 variant was identified in another patient along with the ABCC9 (c.2200G>A; p.V734I) variant, associated with cardiomyopathy. A third harbored the SCN5A variant c.659C>T; p.T220I affecting the nodal rhythm and the c.10580G>A; p.R3527Q damaging variant in APOB associated with Apolipoprotein B deficiency. A 4^th patient harbored the c.143C>T; p.A48V variant in TRIM63, associated with hypertrophic cardiomyopathy. These patients tended to be younger (50.3±18.7 vs 61.2±16.8 years) and 3/4 patients had no comorbidities.

Conclusions: In this pacemaker population, 21% had first degree relatives with pacemakers. Of nine selected patients, 4 had pathogenetic mutations based on next generation sequencing with our cardiac panel. Our study provides important insight to the genetic component of pathology in the pacemaker clinic.