Valvulopathies and Genetics: Where are We?

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.

Investigating cardiac genetic background in sudden infant death syndrome (SIDS).

Sudden infant death syndrome (SIDS) is still the leading cause of death for newborns in developed countries. The pathophysiological mechanisms have not been fully clarified, but in some of SIDS cases variants of genes associated with inherited cardiac conditions are found. In this study, an analysis of SCD-related genes was performed to determine the prevalence of rare pathogenic (P) or likely pathogenic (LP) variants that could provide an unambiguous explanation for the fatal event. A cohort of 76 SIDS cases underwent Next-Generation Sequencing (NGS) analysis with a custom panel of SCD-related genes. Rare variants were classified according to the guidelines provided by the American College of Medical Genetics and Genomics (ACMG) and the specifications of the ClinGen association. Post-mortem genetic testing identified 50 (65.8%) carriers of at least one variant in SCD genes. 104 rare genetic variants were found, 65.4% in genes encoding structural proteins. Only 4 out of 76 cases (5.3%) hosted at least a P or LP variant found in genes with structural or structural/arrhythmogenic functions (SLC22A5, SCN5A, MYL3and TTN). 99 variants were classified as of uncertain significance (VUS). The difference in the distribution of variants between gene groups by function was not statistically significant (chi square, p = 0,219). Despite this, most of the variants concerned structural genes that were supposed to have a close interaction with ion channels, thus providing an explanation for the arrhythmic event. Segregation analysis, reclassification of VUS variants and identification of new associated genes could clarify the implications of the current findings.

Unexpected complexity in the molecular diagnosis of spastic paraplegia 11.

BACKGROUND: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844). METHODS: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing. RESULTS: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping. CONCLUSION: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.

The importance of variant reinterpretation in inherited cardiovascular diseases: Establishing the optimal timeframe.

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.

Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy.

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.

Homoinjerto de epiplón en paciente con quemadura eléctrica y exposición de hueso

Introducción: las quemaduras son traumas ocasionados, generalmente por exposición térmica, radioactiva, eléctrica o química. Presentación del caso: paciente masculino de 17 años que sufre accidentalmente quemadura eléctrica de alto voltaje. En la mano derecha, por su evolución desfavorable y lesiones hipodérmicas con compromiso vascular fue necesaria la amputación de la mano. A nivel del pie derecho se eliminó el tejido necrótico quedando la falange distal del grueso artejo expuesta. Al lograr un tejido de granulación útil se realiza homoinjerto de epiplón. Discusión: el epiplón es un donador natural de factores de crecimiento. El injerto de epiplón mostró su utilidad para proteger pequeñas partes óseas expuestas, favoreciendo el mejoramiento del tejido de granulación, el control de la infección local y la cicatrización. Conclusiones: la utilización del homoinjerto de epiplón es una alternativa viable para cubrir zonas cruentas pequeñas con hueso expuesto, favoreciendo el tejido de granulación y la cicatrización.

Introduction: burns are trauma caused, usually by thermal, radioactive, electrical, or chemical exposure. Presentation of the case: a 17-year-old male patient accidentally suffers a high voltage electrical burn. In the right hand, due to its unfavorable evolution and hypodermic lesions with vascular compromise, the amputation of the hand was necessary. At the level of the right foot, the necrotic tissue was removed, leaving the distal phalanx of the thick exposed thick finger. Once a useful granulation tissue is achieved, omentum homograft is performed. Discussion: the omentum is a natural donor of growth factors. The omentum graft showed its usefulness to protect small exposed bone parts, favoring the improvement of the granulation tissue, the control of local infection and healing. Conclusions: the use of omental homograft is a viable alternative to cover small bloody areas with exposed bone, favoring granulation tissue and healing.

Introdução: as queimaduras são traumas causados, geralmente por exposição térmica, radioativa, elétrica ou química. Apresentação caso: um paciente do sexo masculino de 17 anos sofre acidentalmente uma queimadura elétrica de alta voltagem. Na mão direita, devido à sua evolução desfavorável e lesões hipodérmicas com comprometimento vascular, foi necessária a amputação da mão. Ao nível do pé direito, o tecido necrótico foi removido, deixando exposta a falange distal da dedo grosso exposto. Uma vez obtido um tecido de granulação útil, o homoenxerto de omento é realizado. Discussão: o omento é um doador natural de fatores de crescimento. O enxerto de omento mostrou sua utilidade na proteção de pequenas partes ósseas expostas, favorecendo a melhora do tecido de granulação, o controle da infecção local e a cicatrização. Conclusões: o uso de homoenxerto de omento é uma alternativa viável para cobrir pequenas áreas cruentas com osso exposto, favorecendo o tecido de granulação e cicatrização.

Homoinjerto de epiplón en paciente con quemadura eléctrica y exposición de hueso / Homograft of omentum in patient with electrical burn and exposure of bone

Introducción: las quemaduras son traumas ocasionados, generalmente por exposición térmica, radioactiva, eléctrica o química. Presentación del caso: paciente masculino de 17 años que sufre accidentalmente quemadura eléctrica de alto voltaje. En la mano derecha, por su evolución desfavorable y lesiones hipodérmicas con compromiso vascular fue necesaria la amputación de la mano. A nivel del pie derecho se eliminó el tejido necrótico quedando la falange distal del grueso artejo expuesta. Al lograr un tejido de granulación útil se realiza homoinjerto de epiplón. Discusión: el epiplón es un donador natural de factores de crecimiento. El injerto de epiplón mostró su utilidad para proteger pequeñas partes óseas expuestas, favoreciendo el mejoramiento del tejido de granulación, el control de la infección local y la cicatrización. Conclusiones: la utilización del homoinjerto de epiplón es una alternativa viable para cubrir zonas cruentas pequeñas con hueso expuesto, favoreciendo el tejido de granulación y la cicatrización(AU)

Introduction: burns are trauma caused, usually by thermal, radioactive, electrical, or chemical exposure. Presentation of the case: a 17-year-old male patient accidentally suffers a high voltage electrical burn. In the right hand, due to its unfavorable evolution and hypodermic lesions with vascular compromise, the amputation of the hand was necessary. At the level of the right foot, the necrotic tissue was removed, leaving the distal phalanx of the thick exposed thick finger. Once a useful granulation tissue is achieved, omentum homograft is performed. Discussion: the omentum is a natural donor of growth factors. The omentum graft showed its usefulness to protect small exposed bone parts, favoring the improvement of the granulation tissue, the control of local infection and healing. Conclusions: the use of omental homograft is a viable alternative to cover small bloody areas with exposed bone, favoring granulation tissue and healing(EU)

Cambios en las características clínico-epidemiológicas de los nuevos casos de infección por el VIH-1 en Castellón (España) y su repercusión en la presentación tardía (1987-2011) / Changes in clinic-epidemiological characteristics of new cases of HIV-1 infection in Castellón (Spain), and its impact on delayed presentation (1987-2011)

OBJETIVO: Describir la evolución de las características clínico-epidemiológicas en una cohorte de pacientes infectados por el VIH-1 en Castellón (España), y su repercusión en la presentación tardía. MÉTODOS: Estudio descriptivo retrospectivo en el que se revisaron datos de la primera visita de pacientes infectados por el VIH-1 que consultaron desde 1987 a 2011. RESULTADOS: Durante el periodo de estudio se produjeron importantes cambios en las características de los 1.001 pacientes que consultaron por primera vez. La edad media pasó de ser de unos 30 años antes de 1996, a situarse alrededor de los 35 tras el periodo 2000-2002. El porcentaje de extranjeros pasó de ser < 2% antes de 1997 a representar el 50% en el periodo 2009-2011, y el de transmisión por drogas parenterales del 92,3% antes de 1988 a < 20% tras el periodo 2003-2005, con un descenso paralelo en la coinfección por VHC. La presentación tardía no experimentó cambios significativos, con una media del 47,1% en el periodo estudiado. Los factores asociados a este retraso en solicitar asistencia fueron: mayor edad, diagnóstico realizado a nivel hospitalario, mayor demora en el tiempo estimado entre infección y diagnóstico serológico, y en el tiempo entre diagnóstico serológico y primera visita. CONCLUSIÓN: En nuestro entorno, la epidemiología del VIH-1 ha cambiado considerablemente desde el inicio de la epidemia. El progresivo retraso en el diagnóstico serológico es una importante causa de la escasa variación en el porcentaje de presentaciones tardías, y evidencia el escaso impacto de las estrategias de diagnóstico precoz

OBJECTIVE: To describe the trend of the clinical and epidemiological characteristics of a cohort of HIV-1 infected patients in Castellón (Spain), and its impact on the delayed presentation. METHODS: Data from HIV-1 infected outpatients presenting for care for the first time between 1987 and 2011 were retrospectively analyzed. RESULTS: There have been significant changes in the characteristics of the 1001 newly presented patients during the period studied. An increase in the mean age was observed (increasing from about 30 years before 1996, to approximately 35 after the 2000-2002 period), as well as an increase in the percentage of immigrants (< 2% before 1997, to 50% in the 2009-2011 period), and a decline in the proportion of intravenous drug use as the main transmission route (changing from being 92.3% before 1988 to below 20% after the 2003-2005 period), together with a decrease in the proportion of hepatitis-C coinfection. The rate of late presentation has not significantly changed, being 47.1% in the period studied. Factors associated with this late presentation were: older age, hospital diagnosis, an increased delay between estimated infection time and diagnosis, and between diagnosis and initial presentation. CONCLUSIONS: The epidemiology of HIV-1 infection in our area has dramatically changed since the beginning of the disease. The increasing delay between estimated infection time and diagnosis is an important cause of the lack of variation in the late presentation rate, and highlights the low impact of early diagnosis strategies

Nuevas herramientas diagnósticas en la genética de la muerte súbita / New genetic diagnostic tests for sudden cardiac death

El estudio a escala genómica de las enfermedades cardiovasculares permite entenderlas mejor para optimizar y dirigir terapias personalizadas. En el desarrollo de la muerte súbita cardiaca destacan dos grandes grupos de enfermedades de gran heterogeneidad genética y fenotípica: las enfermedades estructurales o miocardiopatías y las arritmogénicas o canalopatías. El principal problema de ambos tipos de enfermedad es que a menudo causan la muerte súbita en individuos previamente asintomáticos en los que la muerte súbita cardiaca es la primera manifestación de cardiopatía en un alto número de casos. Por consiguiente, y dado que se trata de enfermedades hereditarias, hay un elevado riesgo para los familiares que, pese permanecer asintomáticos, podrían ser portadores de variantes genéticas de riesgo. Se han descrito alrededor de 100 genes implicados en las enfermedades asociadas a muerte súbita cardiaca. La capacidad de la secuenciación convencional de genes Sanger es limitada con respecto a las nuevas opciones tecnológicas en constante desarrollo, tales como los arrays de resecuenciación y especialmente la secuenciación masiva en paralelo, next generation sequencing. Gracias a la mejora de las diferentes químicas en las distintas opciones tecnológicas, los proveedores centran sus esfuerzos en el aumento de la capacidad de generación de datos de estos equipos, así como en la rebaja de los costes de los reactivos necesarios para estos análisis, con objeto de facilitar a la comunidad científica el acceso a estas tecnologías. Dadas la gran cantidad y la complejidad de los datos genéticos derivados de la ultrasecuenciación, que requieren un análisis minucioso de sus implicaciones médicas en todas las ramas de la medicina, es necesaria la creación de centros especializados en el estudio de enfermedades concretas, en el manejo de datos genéticos a gran escala y en prestar asesoramiento genético a las familias (AU)

The study of cardiovascular disease at the genetic level will provide the greater understanding needed for the design and optimization of personalized treatment. The development of sudden cardiac death primarily involves two large groups of disorders that have considerable genetic and phenotypic heterogeneity: the structural disorders or cardiomyopathies and the arrhythmogenic disorders or channelopathy. The principle challenge with both types of disorder is that, in a substantial number of cases, they cause sudden death in previously asymptomatic individuals in whom sudden cardiac death is the first manifestation of cardiac disease. Consequently and given the hereditary nature of the condition, families with asymptomatic family members will be at risk as they could be carriers of a high-risk genetic variant. Around 100 genes have been implicated in conditions associated with sudden cardiac death. The capacity of conventional gene sequencing techniques based on the Sanger method is limited compared with that of the new approaches constantly being developed, such as resequencing arrays and, especially, massively parallel sequencing or next-generation sequencing. Thanks to improvements in the chemicals used in the various sequencing techniques, suppliers have now concentrated their efforts on increasing the data-generating capacity of the technology as well as on reducing the cost of the reagents needed for assays, with the aim of making it easier for the scientific community to access these new techniques. Given the quantity and complexity of the genetic data produced by ultrasequencing, which necessitates meticulous analysis to identify the clinical implications for each branch of medicine, it will be necessary to create specialized centers that can carry out research into specific diseases, manage the large-scale genetic data produced, and provide genetic counseling to families (AU)

Leucostasis pulmonar como primera manifestación de una leucemia mieloide aguda sin hiperleucocitosis / Pulmonary leukostasis as a first manifestation of an acute myeloid leukemia without hyperleukocitosis

No disponible

No disponible

Prevalencia de laxitud articular en una muestra infantil de pacientes escolióticos. análisis de 101 casos consecutivos / Prevalence of articular laxity among pediatric scoliotic patients. Analysis of 101 consecutive cases

Objetivo: Determinar la prevalencia de la laxitud articular en una muestra de chicos visitados en una consulta hospitalaria monográfica de escoliosis.Pacientes y métodos: Se examinaron consecutivamente a 101 pacientes diagnosticados de escoliosis (16 niños y 85 niñas), con una edad media de 13,87 años, que acudían como primera visita a un dispensario monográfico hospitalario de escoliosis. Se utilizaron los criterios de Beighton para evaluar la laxitud articular.Resultados: Un 65,3 por ciento de los pacientes que acudieron a la consulta hospitalaria monográfica de escoliosis tenían laxitud articular. La presencia de laxitud articular no se asoció a diferencias epidemiológicas ni anatómicas entre los pacientes escolióticos.Conclusión: La laxitud articular parece asociarse a la presencia de escoliosis juvenil. (AU)