Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing

Genetic Approaches for the Study of Complex Human Diseases

The field of human genetics has evolved from its initial narrow focus on single-gene Mendelian disorders, which largely affect children, to our current understanding that for most diseases there is continuum of rare to common variants which can exert a range of phenotypic effects. Despite advances in sequencing capabilities and our overall understanding of diseases, there remains a large proportion of heritability unexplained. Through the use of next-generation sequencing technologies and DNA microarray, I have explored a spectrum of genetic variations from rare, single and structural variants to common variants in individuals with i) “lone” atrial fibrillation; ii) familial hypercholesterolemia; and iii) familial partial lipodystrophy. From my research efforts, we implicated rare loss-of-function variants in cardiomyopathy genes to “lone” atrial fibrillation, providing evidence that atrial cardiomyopathy is a genetic sub-phenotype of atrial fibrillation. Additionally, we determined that “lone” atrial fibrillation has a significant accumulation of common variants that together elevate susceptibility to the disease. Also, considering the application of genetics in Medicine, I directly evaluated the increasing responsibility that clinicians have to adjudicate causality of various genetic factors. For instance, having successfully identified a novel apparently pathogenic genetic variant in a family with hypercholesterolemia, I sought to determine its pathogenicity by performing cascade screening and co-segregation analysis in the extended family. My analysis demonstrated that the novel variant was independent of the disease phenotype, preventing a potential misdiagnosis and emphasized the importance of gathering additional confirmatory data in the clinical setting. Further, by studying a well-genotyped and phenotype familial partial lipodystrophy cohort, I uncovered that the prevalence of severe hypertriglyceridemia and its most severe complication, namely acute pancreatitis was more common in affected individuals who had concurrently developed diabetes. In spite of these contributions, significant work remains to explain the full genetic contributions to complex diseases. The benefits of understanding the complete genetic architecture of a disease are potentially immense, allowing advances in pre-symptomatic detection to the development of novel targeted therapies. For the patients this could translate into such benefits as earlier detection, screening for the family, personalized therapies, and a confirmed diagnosis

Association of Human Leukocyte Antigen-G Polymorphisms and Clinical Outcomes Post-transplantation

Human leukocyte antigen (HLA)-G has been shown to inhibit cardiac cells injury in vitro, suggestive of protection against cardiac allograft vasculopathy (CAV). The expression of HLA-G is regulated by single nucleotide polymorphisms (SNPs), and their association with CAV remains unknown. The objective was to determine the association between donor and recipient genotypes and diagnosis of CAV. We retrospectively analyzed 251 heart recipients of whom 196 had their corresponding donors and the association was evaluated with parametric hazard regression models. At 10 years after transplantation, freedom from severe CAV, retransplantation or death was 64% over a mean follow-up of 5.2 ± 3.6 years. In multivariable analysis, the presence of donor-recipient SNP -201 (CC-CC) matching was associated with an increased risk of severe CAV. This is the first investigation to identify an association and it may reveal a pathway to be explored for potential diagnostic and therapeutic strategies for CAV.M.Sc

Educación entre pares, una estrategia para trabajar Chagas desde el aula

Este material, surge como producto de un proyecto de innovación y en el marco de la escuela promotora de salud. Tiene como finalidad contribuir con el desarrollo de un proyecto de educación integral, formando alumnos que sean portadores de mensajes sociales y con capacidad de difundir información, actitudes y pautas de conducta saludables dentro de la comunidad escolar. A partir de la situación problemática planteada en el aula ¿Hay Chagas en la ciudad? , se llevó a cabo una intervención de la currículo escolar. Partiendo de las ideas previas de los alumnos sobre esta temática se buscó aproximarlos a los conocimientos científicos, vincularlos y situarlos en su realidad (escuela, barrio); para luego generar un plan de acción educativo-informativo ideado por ellos mismos, con el principal objetivo de implementar la Educación Entre Pares (EEP) a alumnos del nivel primario o de otros cursos del ni vel medio. Las actividades que se sugieren han sido elaboradas partiendo de la concepción de Escuela, no sólo como un sitio donde se lleva a cabo el proceso de enseñanza-aprendizaje, sino también como punto donde se promueven mensajes, hábitos y acciones relacionado s a la salud. Estas son sólo sugerencias que cada docente deberá adecuar a la situación áulica, disponibilidad y características de la escuela.Fil: Rodriguez, Claudia. Universidad Nacional de Córdoba. Facultad de Cs.exactas Físicas y Naturales. Departamento de Fisiología. Cátedra de Introducción A la Biología; ArgentinaFil: Capdevilla, Valeria. Colegio Nuestra Señora de Loreto de Córdoba; ArgentinaFil: Crocco, Liliana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Duje, Norma. Colegio Nuestra Señora de Loreto de Córdoba; ArgentinaFil: Lazarte, Cecilia Yanina. Instituto Nuestra Señora del Fátima de Córdoba; ArgentinaFil: Lopez, Ana Graciela. Universidad Nacional de Córdoba. Facultad de Cs.exactas Físicas y Naturales. Departamento de Fisiología. Cátedra de Introducción A la Biología; ArgentinaFil: Nattero, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Zulliger, Nora. Instituto Nuestra Señora del Fátima de Córdoba; Argentin

Scientific Overview on CSCI-CITAC Annual General Meeting and 2018 Young Investigators’ Forum

The 2018 Annual General Meeting (AGM) and Young Investigators’ Forum (YIF) of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was held in Toronto, Ontario on November 19–20, 2018, in conjunction with the University of Toronto Clinician Investigator Program Research Day. The theme for the meeting was “Prepare for Success—Things to Master Now for Clinician Scientists in Training”; with lectures and workshops that were designed to provide knowledge and hands-on skills to navigate life as a clinician investigator. The opening remarks were by Jason Berman (President of CSCI), Josh Abraham (President of CITAC/ACCFC) and Nicola Jones (University of Toronto Clinician Investigator Symposium Chair). The keynote speakers were Dr. Ruth Ann Marrie (University of Manitoba), who received the Distinguished Scientist Award, Dr. Davinder Jassal (University of Manitoba), who received the CSCI-RCPSC Henry Friesen Award, and Dr. Aleixo Muise (University of Toronto), who received the Joe Doupe Young Investigator Award. Dr. Minna Woo (University of Toronto), Canada Research Chair in Diabetes Signal Transduction, delivered the keynote lecture “From Onion Cells to Single Cell Seq—A Constant Change in Lenses: A perspective of an evolving clinician scientist”. The workshops, focusing on career development for clinician-scientists, were hosted by Drs. Robert Chen, Stephen Juvet, Lorraine Kalia, Phyllis Billia, Neil Goldenberg, Nicola Jones, Srdjanaa Filipovic, Jason Berman, Josh Abraham, Melanie Szweras, Joseph Ferenbok and Uri Tabori. The AGM also included presentations from clinician investigator trainees from across the country, and these abstracts are summarized in this review. Over 80 abstracts were showcased at this year’s meeting during the poster session, with six outstanding abstracts selected for oral presentations during the President’s Forum

LMNA Variants and Risk of Adult-Onset Cardiac Disease

Background: Genetic variants in LMNA may cause cardiac disease, but population-level contributions of variants to cardiac disease burden are not well-characterized. Objectives: We sought to determine the frequency and contribution of rare LMNA variants to cardiomyopathy and arrhythmia risk among ambulatory adults. Methods: We included 185,990 UK Biobank participants with whole-exome sequencing. We annotated rare loss-of-function and missense LMNA variants for functional effect using 30 in silico prediction tools. We assigned a predicted functional effect weight to each variant and calculated a score for each carrier. We tested associations between the LMNA score and arrhythmia (atrial fibrillation, bradyarrhythmia, ventricular arrhythmia) or cardiomyopathy outcomes (dilated cardiomyopathy and heart failure). We also examined associations for variants located upstream vs downstream of the nuclear localization signal. Results: Overall, 1,167 (0.63%) participants carried an LMNA variant and 15,079 (8.11%) had an arrhythmia or cardiomyopathy event during a median follow-up of 10.9 years. The LMNA score was associated with arrhythmia or cardiomyopathy (OR: 2.21; P < 0.001) and the association was more significant when restricted to variants upstream of the nuclear localization signal (OR: 5.05; P < 0.001). The incidence rate of arrhythmia or cardiomyopathy was 8.43 per 1,000 person-years (95% CI: 6.73-10.12 per 1,000 person-years) among LMNA variant carriers and 6.38 per 1,000 person-years (95% CI: 6.27-6.50 per 1,000 person-years) among noncarriers. Only 3 (1.2%) of the variants were reported as pathogenic in ClinVar. Conclusions: Middle-aged adult carriers of rare missense or loss-of-function LMNA variants are at increased risk for arrhythmia and cardiomyopathy

Overview of the Canadian Clinician Investigator Trainees’ research presented at the 2019 CSCI-CITAC Joint Meeting

The 2019 Annual General Meeting and Young Investigators’ Forum of the Canadian Society for Clinical Investigation / Société Canadienne de Recherche Clinique (CSCI/SCRC) and Clinician Investigator Trainee Association of Canada / Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was held in Banff, Alberta on November 8–10th, 2019. The theme was “Positioning Early Career Investigators for Success: Strategy and Resilience”. Lectures and workshops provided knowledge and tools to facilitate the attendees’ development as clinician investigators. Dr. Jason Berman (President of CSCI/SCRC), Elina Cook (President of CITAC/ACCFC) and Drs. Doreen Rabi and Zelma Kiss (University of Calgary Organizing Co-Chairs) gave opening presentations. The keynote speakers were Dr. William Foulkes (McGill University) (Distinguished Scientist Award winner) and Dr. Andrés Finzi (Université de Montréal) (Joe Doupe Young Investigator Award winner). Dr. Robert Bortolussi (Dalhousie University) received the Distinguished Service Award for his work as the Editor-in-Chief of Clinical and Investigative Medicine and for being instrumental in the development of the Canadian Child Health Clinician Scientist Program. This meeting was the first to host a panel discussion with Drs. Stephen Robbins and Marcello Tonelli from the Canadian Institutes of Health Research. Workshops on communication, career planning and work-life balance were hosted by André Picard and Drs. Todd Anderson, Karen Tang, William Ghali, May Lynn Quan, Alicia Polachek and Shannon Ruzycki. The AGM showcased 90 presentations from clinician investigator trainees from across Canada. Most of the abstracts are summarized in this review. Eight outstanding abstracts were selected for oral presentation at the President’s Forum

Flores del centro de Argentina: Una guía ilustrada para conocer 141 especies típicas

Este libro contiene una selección de 141 especies, nativas y algunas naturalizadas, pertenecientes a 50 familias de Angiospermas que son frecuentes en el Centro de Argentina y especialmente en la Provincia de Córdoba. Se hace una descripción general de cada familia, ilustrando aquellas cuya morfología floral, por ser muy compleja, requiere de una explicación adicional. Se proporciona para cada especie su nombre científico y nombres vulgares, una descripción de su distribución geográfica en el país, hábitat, características morfológicas vegetativas y reproductivas, época de floración, usos más comunes y aspectos notables de su biología. Se destaca de esta obra la ilustración de cada especie con fotografías a color y un glosario ilustrado para facilitar la comprensión de las descripciones. Con este libro pretendemos transmitir los conocimientos generados en los ámbitos académicos con un lenguaje apropiado no sólo para profesionales y estudiantes sino también, y especialmente, para el público en general que tenga interés por las plantas nativas.Fil: Sersic, Alicia Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Cocucci, Andrea Aristides. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Benitez-Vieyra, Santiago Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Cosacov Martinez, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Díaz, Lucrecia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Glinos, Evangelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Grosso, Andrea Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Lazarte, Cecilia Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Medina, Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: More, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Moyano, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Nattero, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Paiaro, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Trujillo, Cecilia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Wiemer, Ana Pia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; Argentin

Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass

Left ventricular mass is a risk marker for cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance is the gold-standard for left ventricular mass estimation, but is challenging to obtain at scale. Here, we use deep learning to enable genome-wide association study of cardiac magnetic resonance-derived left ventricular mass indexed to body surface area within 43,230 UK Biobank participants. We identify 12 genome-wide associations (1 known at TTN and 11 novel for left ventricular mass), implicating genes previously associated with cardiac contractility and cardiomyopathy. Cardiac magnetic resonance-derived indexed left ventricular mass is associated with incident dilated and hypertrophic cardiomyopathies, and implantable cardioverter-defibrillator implant. An indexed left ventricular mass polygenic risk score ≥90th percentile is also associated with incident implantable cardioverter-defibrillator implant in separate UK Biobank (hazard ratio 1.22, 95% CI 1.05-1.44) and Mass General Brigham (hazard ratio 1.75, 95% CI 1.12-2.74) samples. Here, we perform a genome-wide association study of cardiac magnetic resonance-derived indexed left ventricular mass to identify 11 novel variants and demonstrate that cardiac magnetic resonance-derived and genetically predicted indexed left ventricular mass are associated with incident cardiomyopathy

Cardiac ryanodine receptor calcium release deficiency syndrome

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies