A Novel DLG1 Variant in a Family with Brugada Syndrome: Clinical Characteristics and In Silico Analysis

Abstract

Background: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated to sudden cardiac death. Overall, variants have been identified in eighteen genes encoding for ion channel subunits and seven genes for regulatory proteins. Recently, a missense variant in DLG1 has been found within a BrS phenotype-positive patient. DLG1 encodes for synapse associated protein 97 (SAP97), a protein characterized by the presence of multiple domains for protein–protein interactions including PDZ domains. In cardiomyocytes, SAP97 interacts with Nav1.5, a PDZ binding motif of SCN5A and others potassium channel subunits. Aim of the Study: To characterize the phenotype of an Italian family with BrS syndrome carrying a DLG1 variant. Methods: Clinical and genetic investigations were performed. Genetic testing was performed with whole-exome sequencing (WES) using the Illumina platform. According to the standard protocol, a variant found by WES was confirmed in all members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using in silico prediction of pathogenicity. Results: The index case was a 74-year-old man with spontaneous type 1 BrS ECG pattern that experienced syncope and underwent ICD implantation. WES of the index case, performed assuming a dominant mode of inheritance, identified a heterozygous variant, c.1556G>A (p.R519H), in the exon 15 of the DLG1 gene. In the pedigree investigation, 6 out of 12 family members had the variant. Carriers of the gene variant all had BrS ECG type 1 drug induced and showed heterogeneous cardiac phenotypes with two patients experiencing syncope during exercise and fever, respectively. The amino acid residue #519 lies near a PDZ domain and in silico analysis suggested a causal role for the variant. Modelling of the resulting protein structure predicted that the variant disrupts an H-bond and a likelihood of being pathogenic. As a consequence, it is likely that a conformational change affects protein functionality and the modulating role on ion channels. Conclusions: A DLG1 gene variant identified was associated with BrS. The variant could modify the formation of multichannel protein complexes, affecting ion channels to specific compartments in cardiomyocytes.

De Novo p.Asp3368Gly Variant of Dystrophin Gene Associated with X-Linked Dilated Cardiomyopathy and Skeletal Myopathy: Clinical Features and In Silico Analysis

“…We performed exome sequencing and analysis as previously described [ 17 ]. In brief, DNA was isolated from venous blood samples using the Automated Extraction Instruments, MagCore ® Plus II (Diatech Pharmacogenetics, Iesi, Italy) according to manufacturer instructions.…”

Investigation of a Large Kindred Reveals Cardiac Calsequestrin (CASQ2) as a Cause of Brugada Syndrome

“…WES and analysis were carried out as previously reported above [10]. Briefly, DNA was extracted from whole blood samples using the automated extraction instrument MagCore ® Plus II according to the manufacturer's instructions.…”

“…Following that, the Genome Analysis Toolkit (GATK 1.6) was used to process the raw data. Using the BaseSpace Variant Interpreter software, Version 2.17.0.60 (Illumina, San Diego, CA, USA), the reads were aligned to the human genome (GRCh37), and variant calling was completed [10].…”

“…Our team recently discovered a novel DLG1 variant in the BrS family. Mutations in the DLG1 gene may alter the structure of the multichannel protein complex, resulting in structural changes that affect the protein's function and its ability to regulate ion channels [10]. The introduction of new NGS technologies, whole-exome and whole-genome sequencing, allowed the identification of new genes by analyzing WES data from patients with comparable clinical characteristics with high accuracy and reduced cost.…”