Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Mutations in SERPING1, the gene that encodes C1-INH (C1 esterase inhibitor), are responsible for the majority of cases of hereditary angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases the vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. Moreover, a dominantly inherited disease has been described that has a similar clinical picture to C1-INH-HAE (Hereditary angioedema due to C1 inhibitor deficiency), but with normal C1-INH level and activity. This new type of HAE has no mutation in the SERPING1 gene and it is classified as nC1-INH-HAE (HAE with normal C1-INH). Currently mutations in six different genes have been identified as causing nC1-INH-HAE: factor XII (F12), plasminogen (PLG), angiopoietin 1 (ANGPT1), Kininogen 1 (KNG1), Myoferlin (MYOF), and heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6). In this review we aim to summarize the recent advances in genetic characterization of angioedema and possible future prospects in the identification of new genetic defects in HAE. We also provide an overview of diagnostic applications of genetic biomarkers using NGS technologies (Next Generation Sequencing).

Background: Essential tremor (ET) is one of the more common movement disorders. Current diagnosis is solely based on clinical findings. ET appears to be inherited in an autosomal dominant pattern. Several loci on specific chromosomes have been studied by linkage analysis, but the causes of essential tremor are still unknown in many patients. Genetic studies described the association of several genes with familial ET. However, they were found only in distinct families, suggesting that some can be private pathogenic variants. Aim of the Study: to characterize the phenotype of an Italian family with ET and identify the genetic variant associated. Methods: Clinical and genetic examinations were performed. Genetic testing was done with whole-exome sequencing (WES) using the Illumina platform. Bidirectional capillary Sanger sequencing was used to investigate the presence of variant in all affected members of the family. In silico prediction of pathogenicity was used to study the effect of gene variants on protein structure. Results: The proband was a 15-year-old boy. The patient was the first of two children of a non-consanguineous couple. Family history was remarkable for tremor in the mother line. His mother suffered from bilateral upper extremity kinetic tremors (since she was 20 years old), anxiety, and depression. Other relatives referred bilateral upper extremity tremors. In the index case, WES analysis performed supposing a dominant mode of inheritance, identified a novel heterozygous missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) (NM_021614.3: c.1145G>A, p.Gly382Asp). In the pedigree investigation, all carriers of the gene variant had ET and showed variable expressivity, the elder symptomatic relative showing cognitive impairment and hallucinations in the last decade, in addition to tremor since a young age. The amino acid residue #382 is located in a transmembrane region and in silico analysis suggested a causative role for the variant. Modelling of the mutant protein structure showed that the variant causes a clash in the protein structure. Therefore, the variant could cause a conformational change that alters the ability of the protein in the modulation of ion channels Conclusions: The KCNN2 gene variant identified could be associated with ET. The variant could modify a voltage-independent potassium channel activated by intracellular calcium.

Over the last decades, the relevance of genetics in cardiovascular diseases has expanded, especially in the context of cardiomyopathies. Its relevance extends to the management of patients diagnosed with heart failure (HF), given its capacity to provide invaluable insights into the etiology of cardiomyopathies and identify individuals at a heightened risk of poor outcomes. Notably, the identification of an etiological genetic variant necessitates a comprehensive evaluation of the family lineage of the affected patients. In the future, these genetic variants hold potential as therapeutic targets with the capability to modify gene expression. In this complex setting, collaboration among cardiologists, specifically those specializing in cardiomyopathies and HF, and geneticists becomes paramount to improving individual and family health outcomes, as well as therapeutic clinical results. This review is intended to offer geneticists and cardiologists an updated perspective on the value of genetic research in HF and its implications in clinical practice.

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.