Identification by Whole Genome Sequencing of a New Gene Causing Hereditary Sinus Node and Atrioventricular Conduction Dysfunction

Introduction Hereditary sinus node dysfunction (SND) with atrioventricular block (AVB) is a rare disease characterized by permanent heart rate decrease associated with paroxysmal dizziness and syncope. Pacemaker implantation remains the main therapy. To date, only few genes are known associated with this disease. Most of the cases remain genetically unsolved. Objective The aim of the study is to identify a new gene responsible for familial sinus node and atrioventricular conduction dysfunction (SND +AVB). Methods A genome-wide linkage analysis is performed to map the SND + AVB locus and is completed by performing Whole Genome Sequencing (WGS). Candidate variants (Single Nucleotide Variants (SNV) and Copy Number Variations (CNV) will be kept if rare and shared by affected members. Results We investigated a 4 generations pedigree with 25 family members, 13 of them were affected or probably affected by an autosomal dominant SND + AVB. The mean age of cardiac pacemaker implantation was 42 years old, the youngest of them had at 25 years old. Among the family WGS was performed in two first cousins. We exclude the presence of rare variants among the gene previously associated with SND or AVB. Conclusion Our results suggest the presence of the mutation in a new gene. Thanks to the linkage analysis we may isolate a region associated with the phenotype and then identify candidate rare variant shared by the 2 affected members whole genome sequenced. Such candidate variants will be tested in other affected family members, prioritized according tissue expression and pathogenicity prediction.