A. Topological diagram of Nav1.5 showing the location of D1816 residue. H1 to H6: each of the six α-helices present in the proximal half of the C-terminus. IQ: IQ motif which constitutes a calmodulin binding site. PY: PY motif which constitutes a binding site for E3 ubiquitin-protein ligases. PDZ: PDZ motif which constitutes a binding site for SAP97, PTPH1, and syntrophins. B. Sequence alignments of a segment of the C-terminus of SCN5A homologs in 7 different species and SCNXA family sodium channel expressed in human tissues. The sequence of p.D1816VfsX7 mutation is also shown. The respective accession numbers are NP_001159435.1, NP_001035232.1, NP_001075145.1, NP_000325.4, NP_000326.2, NP_002967.2, NP_001171455.1, and NP_002968.1 for SCN1-5/7-9, and for the different species are: XP_001171891.2 (Pan troglodytes), NP_001240789.1 (Mus musculus), NP_001153634.1 (Rattus norvegicus), NP_776883.1 (Bos taurus), NP_001157367.1 (Equus caballus), and XP_001232818.2 (Gallus gallus). “*” means that the residues in that column are identical in all the sequences in the alignment. “:”indicates conservation between groups of strongly similar properties. “.”indicates conservation between groups of weakly similar properties. C. DNA sequence chromatograms of the proband depicting the heterozigous insertion in exon 28 of SCN5A.