Great clinical variability of Nance Horan syndrome due to deleterious NHS mutations in two unrelated Spanish families.

Background: Nance-Horan syndrome (NHS) is an X-linked rare congenital disorder caused by mutations in the NHS gene. Clinical manifestations include congenital cataracts, facial and dental dysmorphism and, in some cases, intellectual disability. The aim of the present work was to identify the genetic cause of this disease in two unrelated Spanish NHS families and to determine the relative involvement of this gene in the pathogenesis.Materials and methods: Four members of a two-generation family, three males and one female (Family 1), and seven members of a three-generation family, two males and five females (Family 2) were recruited and their index cases were screened for mutations in the NHS gene and 26 genes related with ocular congenital anomalies by NGS (Next Generation Sequencing).Results: Two pathogenic variants were found in the NHS gene: a nonsense mutation (p.Arg373X) and a frameshift mutation (p.His669ProfsX5). These mutations were found in the two unrelated NHS families with different clinical manifestations.Conclusions: In the present study, we identified two truncation mutations (one of them novel) in the NHS gene, associated with NHS. Given the wide clinical variability of this syndrome, NHS may be difficult to detect in individuals with subtle clinical manifestations or when congenital cataracts are the primary clinical manifestation which makes us suspect that it can be underdiagnosed. Combination of genetic studies and clinical examinations are essential for the clinical diagnosis optimization.

Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug-induced arrhythmia and sudden unexplained deaths

ABSTRACT: Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using mediumthroughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity. (AU)

Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug-induced arrhythmia and sudden unexplained deaths.

Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity.

Necesidades docentes en Evaluación y Prevención del Riesgo Tóxico: de la Toxicología Experimental a la Reguladora / Educational needs in Toxic Prevention and Risk Assessment: From experimental to Regulatory Toxicology

Se revisan las necesidades formativas para una serie de raas aplicadas de la toxicología derivadas de las áreas fundamentales mecanística y de evaluación toxicológica, que comprenden fundamentalmente la toxicología de sistemas, la evaluación del riesgo y la toxicología reguladora. Son materias necesarias para el desempeño profesional en los organismos nacionales, autonómicos y locales responsables de la regulación e inspección de la comercialización y uso de compuestos industriales, medicamentos, productos cosméticos, alimentarios o fitosanitarios, o de contaminantes ambientales o laborales, así como en industrias y consultorías. Se han identificado más de 25 actividades científicas de gran relevancia realizadas en España desde 1995, con una media de 1,6 actividades por año. Los principales grados de las ciencias de la salud incluyen una asignatura troncal de Toxicología, que puede aparecer como optativa en otros, generalmente de 6 créditos ECTS, con un programa muy uniforme, que incluye entre sus descriptores la estimación del riesgo, la evaluación toxicológica, el empleo de métodos alternativos y las bases de la toxicología reguladora. En relación con los estudios de postgrado, se identifican másteres con una gran variedad de contenidos y enfoques, que en algunos casos cubren un abanico muy amplio de disciplinas, incluyendo las toxicológicas, así como otros que cubren las áreas específicas de la toxicología. De la revisión transversal de los programas docentes de pregrado, postgrado y doctorado en España, se deduce la paulatina adaptación al EEES y la adecuada inclusión en los mismos de materias sobre evaluación experimental de la toxicidad, prevención del riesgo tóxico y toxicología reguladora (AU)

The training needs for a range of applied toxicology branches arising from the fundamental areas of mechanistic and toxicological evaluation, which mainly comprise of systems toxicology , risk assessment and regulatory toxicology , are reviewed. Thet are necessary for professional performance in national, regional and local authorities responsible for regulation and inspection of the marketing and use of industrial chemicals, pharmaceuticals, cosmetics, food or plant protection products or environmental or occupational pollutants, as well as industries and consultancies. There are more than 25 highly relevant scientific activities carried out in Spain since 1995, with an average of 1.6 activities per year . The main bachelor's degrees of the health sciences include a very uniform obligatory subject of T oxicology , which may appear as an option in others, usually with 6 ECTS credits, which includes among its descriptors risk e stimation assessment toxicology, the use of alternative methods and the basis for regulatory toxicology. In relation to postgraduate studies, masters were identified with a variety of topics and approaches, which in some cases cover a very wide range of disciplines, including toxicology and other covering in depth the specific toxicologic areas. From the transversal review of the teaching programs at under graduate, graduate and doctoral degrees in Spain, it was deduced a gradual adaptation to the EHEA and the appropriate inclusion of subjetcs on experimental evaluation of toxicity , toxic hazard prevention and regulatory toxicology (AU)