Single Cell Transcriptomics Trajectory and Molecular Convergence of Clinically Relevant Mutations in Brugada Syndrome

Am J Physiol Heart Circ Physiol. 2021 Apr 2. doi: 10.1152/ajpheart.00061.2021. Online ahead of print.ABSTRACTBrugada syndrome (BrS) is a rare, inherited arrhythmia with high risk of sudden cardiac death. To evaluate the molecular convergence of clinically relevant mutations and to identify developmental cardiac cell types that are associated with BrS etiology, we collected 733 mutations represented by 16 sodium, calcium, potassium channels, regulatory and structural genes related to BrS. Among the clinically relevant mutations, 266 are unique singletons and 88 mutations are recurrent. We observed an over representation of clinically relevant mutations (~80%) in SCN5A gene, and also identified several candidate genes, including GPD1L, TRPM4 and SCN10A. Furthermore, protein domain enrichment analysis revealed that a large proportion of the mutations impacted ion-transport domains in multiple genes, including SCN5A, TRPM4 and SCN10A. A comparative protein domain analysis of SCN5A further established a significant (p=0.04) enrichment of clinically relevant mutations within ion-transport domain, including a significant (p=0.02) mutation hotspot within 1321-1380 residue. The enrichment of clinically relevant mutations within SCN5A ion transport domain is stronger (p=0.00003) among early onset of BrS. Our spatiotemporal cellular heart developmental (prenatal to adult) trajectory analysis applying single cell transcriptome identified the most frequently BrS mutated genes (SCN5A and G...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Source Type: research