Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the ...identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.
La presencia de las lenguas minoritarias en los sistemas educativos está vinculada al contexto sociopolítico y cultural en el que se sitúa. Por lo tanto, es necesario cuestionarse qué posición ocupan ...en relación con las lenguas estatales y cómo se produce su convivencia, generalmente jerarquizada, en los ámbitos de uso públicos. Aplicando una metodología específica para la educación comparada, presentada en cuatro fases: descripción, interpretación, yuxtaposición y comparación, analizaremos si los modelos de planificación lingüística adoptados en las unidades de comparación escogidas apuestan por el ecologismo lingüístico. La organización idiomática adecuada en contextos caracterizados por el contacto de lenguas resulta fundamental si consideramos que el input en los ámbitos de uso públicos se encuentra dominado por la lengua mayoritaria y, por tanto, se merma la posibilidad de acceso a modelos lingüísticos válidos diferentes al de las lenguas de poder. Es por ello por lo que hay que analizar la planificación lingüística de las mismas en la enseñanza al ser crucial para equilibrar esta situación. Así, hemos realizado un análisis comparado entre los sistemas educativos de los territorios con lenguas propia en España, Francia y Letonia para conocer si estos programas dan una respuesta efectiva a las necesidades del alumnado: el desarrollo de las habilidades comunicativas, como eje central para la construcción del aprendizaje, y la garantía de los derechos lingüísticos, como derechos humanos de las minorías en coordenadas bilingües.
Valvulopathies and Genetics: Where are We? Coll, Mònica; Fernández-Falgueras, Anna; Iglesias, Anna ...
Reviews in cardiovascular medicine,
2024, Letnik:
25, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Valvulopathies are among the most common cardiovascular diseases, significantly increasing morbidity and mortality. While many valvular heart diseases are acquired later in life, an important genetic ...component has been described, particularly in mitral valve prolapse and bicuspid aortic valve. These conditions can arise secondary to genetic syndromes such as Marfan disease (associated with mitral valve prolapse) or Turner syndrome (linked to the bicuspid aortic valve) or may manifest in a non-syndromic form. When cardiac valve disease is the primary cause, it can appear in a familial clustering or sporadically, with a clear genetic component. The identification of new genes, regulatory elements, post-transcriptional modifications, and molecular pathways is crucial to identify at-risk familial carriers and for developing novel therapeutic strategies. In the present review we will discuss the numerous genetic contributors of heart valve diseases.
Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, ...although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.
Sudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of ...relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases.
Our cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively.
Cardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk.
The olive tree (Olea europaea L.) has been cultivated around the Mediterranean basin since ancient times, ‘Arbequina’ being one of the most widely grown varieties. To improve the knowledge on ...ripening-related firmness changes in olive fruit, cell wall metabolism was studied in irrigated and rain-fed ‘Arbequina’ olives grown at ‘Les Garrigues’, a Protected Designation of Origin (PDO) in Catalonia (NE Spain) where harsh environmental conditions occur during fruit development. Fruit samples were picked periodically from September to January. Time-course dynamics of firmness loss during maturation were characterised by a first phase of rapid firmness loss followed by a second phase of moderate change. Compositional changes in cell walls and related enzyme activities were studied in fruit samples. Fruit firmness was significantly higher in rain-fed than in irrigated olives. Neutral sugar loss, an early event in ripening-related cell wall modifications, was lower in rain-fed samples, which, moreover, retained higher uronic acid amounts in the chelator-soluble fraction, thus resulting in attenuated firmness loss in these fruits.
Olive (Olea europaea L.) fruit and derived products play a pivotal role in the Mediterranean diet, to which they contribute their gastronomic value and their health-promoting properties. The fruit ...cuticle constitutes the interface between the plant and the surrounding environment, and it modulates relevant traits such as water loss, mechanical resistance, and susceptibility to pests and rots. Hence, a better knowledge of fruit cuticle properties and the impact thereupon of agronomic factors could help improving olive grove management. In this work, time–course changes in fruit cuticle yields and composition were assessed during the on-tree ripening of ‘Arbequina’ olives obtained from irrigated or rain-fed trees grown at a commercial grove located in El Soleràs (Catalonia, Spain), where low annual rainfall occur together with cold winters and hot dry summers. Significantly higher wax contents were observed for rain-fed than for irrigated fruits, both in relative (% over total cuticle) and in absolute terms (from 231 to 840 µg cm−2 and from 212 to 560 µg cm−2, respectively, contingent upon the maturity stage), in agreement with their proposed role as a barrier against water loss. Compositional differences in cuticular waxes and in cutin monomers were also detected between irrigated and rain-fed olives, with major changes involving significantly higher loads per surface area of triterpenoids and ω-hydroxy fatty acids in the latter. In contrast to the load and composition of cuticular wax, no apparent impact of irrigation was observed on either total cuticle yields or cuticle thickness.
Sudden unexpected death in epilepsy is an unpredicted condition in patients with a diagnosis of epilepsy, and autopsy does not conclusively identify cause of death. Although the pathophysiological ...mechanisms that underlie this entity remain unknown, the fact that epilepsy can affect cardiac function is not surprising. The genetic factors involving ion channels co-expressed in the heart and brain and other candidate genes have been previously described. In the present study, 20 epilepsy patients with personal or family history of heart rhythm disturbance/cardiac arrhythmias/sudden death were sequenced using a custom re-sequencing panel. Twenty-six relatives were genetically analysed to ascertain the family segregation in ten individuals. Four subjects revealed variants with positive genotype-phenotype segregation: four missense variants in the CDKL5, CNTNAP2, GRIN2A and ADGRV1 genes and one copy number variant in KCNQ1. The potential pathogenic role of variants in new candidate genes will need further studies in larger cohorts, and the evaluation of the potential pathogenic role in the cardio-cerebral mechanisms requires in vivo/in vitro studies. In addition to family segregation, evaluation of the potential pathogenic roles of these variants in cardio-cerebral mechanisms by in vivo/in vitro studies should also be performed. The potential pathogenic role of variants in new candidate genes will need further studies in larger cohorts.
Dilated cardiomyopathy is a heterogeneous entity that leads to heart failure and malignant arrhythmias. Nearly 50% of cases are inherited; therefore, genetic analysis is crucial to unravel the cause ...and for the early identification of carriers at risk. A large number of variants remain classified as ambiguous, impeding an actionable clinical translation. Our goal was to perform a comprehensive update of variants previously classified with an ambiguous role, applying a new algorithm of already available tools. In a cohort of 65 cases diagnosed with dilated cardiomyopathy, a total of 125 genetic variants were classified as ambiguous. Our reanalysis resulted in the reclassification of 12% of variants from an unknown to likely benign or likely pathogenic role, due to improved population frequencies. For all the remaining ambiguous variants, we used our algorithm; 60.9% showed a potential but not confirmed deleterious role, and 24.5% showed a potential benign role. Periodically updating the population frequencies is a cheap and fast action, making it possible to clarify the role of ambiguous variants. Here, we perform a comprehensive reanalysis to help to clarify the role of most of ambiguous variants. Our specific algorithms facilitate genetic interpretation in dilated cardiomyopathy.
Molecular screening for pathogenic mutations in sudden cardiac death (SCD)-related genes is common practice for SCD cases. However, test results may lead to uncertainty because of the identification ...of variants of unknown significance (VUS) occurring in up to 70% of total identified variants due to a lack of experimental studies. Genetic variants affecting potential splice site variants are among the most difficult to interpret. The aim of this study was to examine rare intronic variants identified in the exonic flanking sequence to meet two main objectives: first, to validate that canonical intronic variants produce aberrant splicing; second, to determine whether rare intronic variants predicted as VUS may affect the splicing product. To achieve these objectives, 28 heart samples of cases of SCD carrying rare intronic variants were studied. Samples were analyzed using 85 SCD genes in custom panel sequencing. Our results showed that rare intronic variants affecting the most canonical splice sites displayed in 100% of cases that they would affect the splicing product, possibly causing aberrant isoforms. However, 25% of these cases (1/4) showed normal splicing, contradicting the in silico results. On the contrary, in silico results predicted an effect in 0% of cases, and experimental results showed >20% (3/14) unpredicted aberrant splicing. Thus, deep intron variants are likely predicted to not have an effect, which, based on our results, might be an underestimation of their effect and, therefore, of their pathogenicity classification and family members’ follow-up.
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