SCN5A overlap syndromes: An open-minded approach.

SCN5A overlap syndromes are clinical entities that express a phenotype combining aspects of different canonical SCN5A-related arrhythmia syndromes or a variable arrhythmic phenotype among individuals carrying the same SCN5A mutation. Here we review the literature addressing SCN5A overlap syndromes as well as the principal mechanisms currently proposed. Among others, a multifactorial determination encompassing an interaction between SCN5A variant(s), other genetic polymorphisms, and possibly environmental factors seems the most plausible hypothesis.

[Sinus node dysfunction, Brugada syndrome and long QT syndrome affecting the same patient†: when genetics can't make head or tail of it]. / Dysfonction sinusale, syndrome de Brugada et syndrome du QT long chez un même patient - Quand la génétique y perd son latin.

The gene SCN5A encodes the cardiac sodium channel which, through the conduction of Na+ current into the cell, generates the fast upstroke of the action potential of cardiomyocytes. Pathogenic variants of SCN5A have been causally associated to several hereditary cardiac diseases including, among others, Brugada syndrome, congenital long QT syndrome and sinus node dysfunction. Recently, overlap syndromes have been described that are characterized by the simultaneous expression of mixed clinical phenotypes among two or more hereditary cardiac diseases associated to the gene SCN5A (HCD-SCN5A). For this reason, it is time to rethink about HCD-SCN5A as different expressions of the same complex spectrum encompassing multiple clinical phenotypes with pronounced overlaps instead of as distinct clinical entities.

Le gène SCN5A code pour le canal sodique cardiaque qui est responsable de la pente de dépolarisation rapide du potentiel d'action. Plusieurs cardiopathies héréditaires (CH) ont été associées à des variants pathogènes du gène SCN5A incluant, entre autres, le syndrome de Brugada, le syndrome du QT long congénital et la dysfonction sinusale. Récemment, des syndromes de chevauchement ont été également décrits, s'exprimant, chez un même patient, par un phénotype clinique mixte comprenant une combinaison des manifestations rapportées ci-dessus. Dans ce contexte, nous devrions donc reconsidérer cliniquement les CH impliquant le gène SCN5A comme des expressions différentes d'un même éventail de phénotypes cliniques avec chevauchements marqués plutôt que comme des entités cliniques distinctes et isolées.

A New Variant in the MYH11 Gene in a Familial Case of Thoracic Aortic Aneurysm.

MYH11 (myosin heavy chain 11) gene is involved in vascular contractility and several autosomal dominant mutations have been linked to thoracic aortic aneurysms. Three male members of the same family were found to carry a heterozygous missense variant in the MYH11 gene and all 3 individuals presented a thoracic aortic aneurysm/dilation. We identified a rare missense variant in the MYH11 gene predicted to be damaging and affecting a conserved amino acid in the myosin tail of the protein. This variant appears to be responsible for our familial case of thoracic aortic aneurysms, as the clinical expression reunited all features of genetic aneurysms.

The Global State of the Genetic Counseling Profession.

The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

Consequences of combining siRNA-mediated DNA methyltransferase 1 depletion with 5-aza-2'-deoxycytidine in human leukemic KG1 cells.

5-azacytidine and 5-aza-2'-deoxycytidine are clinically used to treat patients with blood neoplasia. Their antileukemic property is mediated by the trapping and the subsequent degradation of a family of proteins, the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) leading to DNA demethylation, tumor suppressor gene re-expression and DNA damage. Here we studied the respective role of each DNMT in the human leukemia KG1 cell line using a RNA interference approach. In addition we addressed the role of DNA damage formation in DNA demethylation by 5-aza-2'-deoxycytidine. Our data show that DNMT1 is the main DNMT involved in DNA methylation maintenance in KG1 cells and in mediating DNA damage formation upon exposure to 5-aza-2'-deoxycytidine. Moreover, KG1 cells express the DNMT1 protein at a level above the one required to ensure DNA methylation maintenance, and we identified a threshold for DNMT1 depletion that needs to be exceeded to achieve DNA demethylation. Most interestingly, by combining DNMT1 siRNA and treatment with low dose of 5-aza-2'-deoxycytidine, it is possible to uncouple DNA damage formation from DNA demethylation. This work strongly suggests that a direct pharmacological inhibition of DNMT1, unlike the use of 5-aza-2'-deoxycytidine, should lead to tumor suppressor gene hypomethylation and re-expression without inducing major DNA damage in leukemia.

Discovery of the first histone deacetylase 6/8 dual inhibitors.

We disclose the first small molecule histone deacetylase (HDAC) inhibitor (3, BRD73954) capable of potently and selectively inhibiting both HDAC6 and HDAC8 despite the fact that these isoforms belong to distinct phylogenetic classes within the HDAC family of enzymes. Our data demonstrate that meta substituents of phenyl hydroxamic acids are readily accommodated upon binding to HDAC6 and, furthermore, are necessary for the potent inhibition of HDAC8.

Potent and selective inhibition of histone deacetylase 6 (HDAC6) does not require a surface-binding motif.

Hydroxamic acids were designed, synthesized, and evaluated for their ability to selectively inhibit human histone deacetylase 6 (HDAC6). Several inhibitors, including compound 14 (BRD9757), exhibited excellent potency and selectivity despite the absence of a surface-binding motif. The binding of these highly efficient ligands for HDAC6 is rationalized via structure-activity relationships. These results demonstrate that high selectivity and potent inhibition of HDAC6 can be achieved through careful choice of linker element only.

Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries.

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.