A Novel Splice-Site Mutation in the ELN Gene Suggests an Alternative Mechanism for Vascular Elastinopathies.

The ELN gene encodes elastin, a fundamental protein of the extracellular matrix that confers elasticity to different tissues including blood vessels. The formation of elastin fibers is a complex process involving monomer coacervation and subsequent crosslinking. Mutations in exons 1-29 of the ELN gene have been linked to supravalvular aortic stenosis (SVAS) whereas mutations in exons 30-33 are associated with autosomal dominant cutis laxa (ADCL). This striking segregation has led to the hypothesis that distinct molecular mechanisms underlie both diseases. SVAS is believed to arise through haploinsufficiency while ADCL is hypothesized to be caused by a dominant negative effect. Here, we describe a patient with SVAS harboring a novel splice-site mutation in the last exon of ELN. The location of this mutation is not consistent with current knowledge of SVAS, since all mutations reported in the C-terminus have been found in ADCL patients, and a thorough evaluation did not reveal significant skin involvement in this case. RT-PCR analysis of skin tissue showed that C-terminal mutations in the region can lead to the production of aberrant transcripts through intron retention and activation of cryptic splice sites and suggest that disruption of the very last exon can lead to functional haploinsufficiency potentially related to SVAS.

Identification of a New Candidate Locus for Ebstein Anomaly in 1p36.2.

Ebstein anomaly (EA) is a rare congenital heart defect (CHD) with a poorly characterized genetic etiology. However, some EA patients carry deletions in 1p36, all of which have been reported to carry distal deletions and share loss of the PRDM16 gene, which is currently considered the most likely candidate for EA development in this region. Here, we report a patient with an 11.96-Mb proximal 1p36 deletion, without loss of PRDM16, who presented with EA and a proximal deletion phenotype. This finding suggests that PRDM16 loss is not required for the development of EA in 1p36 deletions and that the loss of an additional proximal locus in 1p36 is also likely associated with EA. Our data suggest that a distal locus containing the SKI gene and a proximal locus containing the CHD-associated genes RERE and UBE4B are the most probable etiological factors for EA in patients with 1p36 deletion syndrome.

Identification of clinically relevant phenotypes in patients with Ebstein anomaly.

BACKGROUND: Ebstein anomaly (EA) is a heterogeneous congenital heart defect (CHD), frequently accompanied by diverse cardiac and extracardiac comorbidities, resulting in a wide range of clinical outcomes. HYPOTHESIS: Phenotypic characterization of EA patients has the potential to identify variables that influence prognosis and subgroups with distinct contributing factors. METHODS: A comprehensive cross-sectional phenotypic characterization of 147 EA patients from one of the main referral institutions for CHD in Colombia was carried out. The most prevalent comorbidities and distinct subgroups within the patient cohort were identified through cluster analysis. RESULTS: The most prevalent cardiac comorbidities identified were atrial septal defect (61%), Wolff-Parkinson-White syndrome (WPW; 27%), and right ventricular outflow tract obstruction (25%). Cluster analysis showed that patients can be classified into 2 distinct subgroups with defined phenotypes that determine disease severity and survival. Patients in cluster 1 represented a particularly homogeneous subgroup with a milder spectrum of disease, including only patients with WPW and/or supraventricular tachycardia (SVT). Cluster 2 included patients with more diverse cardiovascular comorbidities. CONCLUSIONS: This study represents one of the largest phenotypic characterizations of EA patients reported. The data show that EA is a heterogeneous disease, very frequently associated with cardiovascular and noncardiovascular comorbidities. Patients with WPW and SVT represent a homogeneous subgroup that presents with a less severe spectrum of disease and better survival when adequately managed. This should be considered when searching for genetic causes of EA and in the clinical setting.

Dilemas éticos de las investigaciones en genética, en el marco de las normativas colombianas que las regulan / Ethical Dilemmas of Research in Genetics, within the Framework of the Colombian Regulations that Regulate them / Dilemas Éticos da Pesquisa em Genética, dentro da Estrutura da Regulamentação Colombiana que os Regulam

Introducción: La investigación en genética representa un campo importante hoy en día en la investigación científica, debido a los recientes avances tecnológicos y su potencial para curar y prevenir enfermedades. Objetivos: Identificar los dilemas éticos más importantes en esta rama de la investigación y las medidas que protegen a los participantes de las investigaciones a escalas nacional e internacional, al compararlas entre sí y relacionarlas con los dilemas éticos planteados, para fomentar la discusión ética del tema y la creación de nuevas políticas sobre la materia. Planteamiento del problema: Se identifican diferentes dilemas éticos, al partir del problema mismo que supone definir qué es la información genética, así como la contraposición entre el derecho a la intimidad y el derecho a la vida, el estrés psicosocial que generan los exámenes y los problemas secundarios al almacenamiento de información por tiempo indefinido en biobancos. Desarrollo del tema: En respuesta a los dilemas éticos expuestos, se han expedido declaraciones internacionales que intentan abordarlos, cuyas pautas deberían estar reflejadas en la legislación de cada nación, por lo cual se revisan las normas que existen en Colombia al respecto y la manera como se debe elaborar un consentimiento informado para este tipo de investigaciones. Discusión y conclusiones: En Colombia se encuentran pocas medidas que regulen este tipo de problemas éticos, lo cual deja a los participantes en investigaciones en genética expuestos a un riesgo de discriminación importante. Por lo tanto, deberían expedirse normas que regulen no solo la investigación genética en Colombia, sino, también, el manejo de los datos genéticos, y prohibir la discriminación genética. De esta manera, las investigaciones estarán menos limitadas y se podrá avanzar en este campo, el cual puede llegar a representar grandes avances en las ciencias de la salud

Background: Genetic research represents today an important field in scientific investigation, due to recent technological advances and its potential to cure and prevent diseases. Objetives: To identify the ethical dilemmas derived from this field of investigation and the national and international norms that regulate them, comparing them and relating them to the ethical dilemmas raised, to promote discussion on these matters and the creation of new measures. Problem statement: Different ethical dilemmas are identified, departing from the problem that rises the definition of genetic information itself, the same as the contrappsosition between the right to intimacy and the right to live, the psychosocial stress derived from the exams and the problems generated from the storage of information by bio-banks for an indefinite time. Development: In response to the ethical dilemmas exposed, international declarations have been issued to face these problems and their principles should be reflected in the legislation of each nation, thus the norms in Colombia concerning these issues are revised, as well as the way an informed consent for this type of research should be made. Discussion and conclusions: In Colombia, there are few measures that regulate this type of ethical dilemmas, which leaves patients exposed to a significant discrimination risk. Thus, measures should be implemented, that not only regulate genetic research in Colombia, but also the management of genetic data and prohibit genetic discrimination. This way, research will be less limited and scientific advances will be possible, in a way that may represent important advances to health-sciences

A pesquisa em genética representa um campo importante atualmente na pesquisa científica, devido aos recentes avanços tecnológicos e seu potencial para curar e prevenir doenças. Objetivos: Identificar os dilemas éticos mais importantes neste ramo de pesquisa e as medidas que protegem os participantes da pesquisa em nível nacional e internacional, comparando-os entre si e relacionando-os a dilemas éticos, para promover a discussão ética do tema e a criação de novas políticas sobre o assunto. Abordagem do problema: diferentes dilemas éticos são identificados, partindo do próprio problema de definir o que é informação genética, bem como o contraste entre o direito à privacidade e o direito à vida, o estresse psicossocial gerado pelos exames e problemas secundários ao armazenamento indefinido de informações em bio-bancos. Desenvolvimento do tema: Em resposta aos dilemas éticos expostos, foram emitidas declarações internacionais que tentam abordá-las, cujas diretrizes devem ser refletidas na legislação de cada nação, razão pela qual as regulamentações na Colômbia são revisadas e a maneira pela qual que um consentimento informado para este tipo de pesquisa deve ser elaborado. Discussão e conclusões: Na Colômbia, existem poucas medidas que regulam esse tipo de problema ético, o que deixa os participantes da pesquisa genética expostos a um risco de discriminação significativa. Portanto, devem ser emitidos regulamentos que regulem não apenas a pesquisa genética na Colômbia, mas também o gerenciamento de dados genéticos e proíbam a discriminação genética. Dessa forma, a pesquisa será menos limitada e o progresso será feito neste campo da ciência, o que pode representar grandesavanços nas ciências da saúde