Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

Background: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. // Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. // Results: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. // Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing

Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives

The sudden death of a young, apparently fit and healthy person is amongst the most challenging scenarios in clinical medicine. Sudden cardiac death (SCD) is a devastating and tragic outcome of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, genetic (inherited) cardiac disorders comprise a substantial proportion of SCD cases aged 40 years and less. This includes the primary arrhythmogenic disorders such as long QT syndromes and inherited cardiomyopathies, namely hypertrophic cardiomyopathy. In up to 30% of young SCD, no cause of death is identified at postmortem, so-called autopsy-negative or sudden arrhythmic death syndrome (SADS). Management of families following SCD begins with a concerted effort to identify the cause of death in the decedent, based on either premorbid clinical details or the pathological findings at postmortem. Where no cause of death is identified, genetic testing of deoxyribonucleic acid extracted from postmortem blood (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Irrespective of the genetic testing considerations, all families in which a sudden unexplained death has occurred require targeted and standardized clinical testing in an attempt to identify relatives who may be at-risk of having the same inherited heart disease and therefore also predisposed to an increased risk of SCD. Optimal care of SCD families therefore requires dedicated and appropriately trained staff in the setting of a specialized multidisciplinary cardiac genetic clini

Girls, Autism Identities, and Education

This chapter reports on a collaborative autoethnography about girls, autism identities, and education. Three researchers who are not autistic and four researchers who identify as autistic investigated how various sociocultural factors influenced development of autistic identity across the school years. The four autistic women documented and shared autobiographical data with the collective about their school experiences and reflections of how these experiences impacted their developing identity. A number of themes emerged from the data that were used to inform the development of a series of propositions to support inclusive practices in schools for autistic girls and nurture their developing identities

Long-Term Arrhythmic Follow-Up and Risk Stratification of Patients With Desmoplakin-Associated Arrhythmogenic Right Ventricular Cardiomyopathy

Background: Patients with likely pathogenic/pathogenic desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting. Objectives: The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with DSP likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria (DSP-TFC+). Methods: DSP-TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics. Results: Among 252 DSP-TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank P = 0.0239). History of nonsustained VT (aHR 2.097; P = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age (P = 0.723) nor male sex (P = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560]). Conclusions: DSP-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP-TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP-TFC+ patients with nonsustained VT should be considered as high-risk.</p

Removing educational barriers in Australian schools for autistic students (REBAS): Current trends, gaps, and recommendations in educational research, inclusive policy, and educational practice

The aim of this white paper is to give readers a better understanding of what is needed for autistic learners to flourish in educational environments. The white paper reports on the findings of the Autism CRC research project titled: Removing Educational Barriers in Australian Schools (REBAS). The aim of the REBAS project was to increase awareness and understanding of educational enablers and barriers for autistic students.The white paper reports on five key areas:1. A summary of the educational body of research conducted by Autism CRC (2013–2022).2. A summary of key findings from the data generated by scoping review research across seven key themes. These reviews were conducted with the aim of reviewing the literature to identify current knowledge and gaps, to provide recommendations for research, policy and practice that will support autistic learners to flourish in their education.3. A summary of key findings from an analysis of inclusive policies across all states and territories of Australia to provide recommendations for progressing nationwide inclusive policy and practice.4. A summary of key results from empirical research conducted nationwide with multiple stakeholders (through a survey and interviews). The focus of the research was identifying educational enablers and barriers for autistic learners and their siblings. 5. Key recommendations to ensure autistic and diverse learners flourish and have agency in their educatio

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy

International audienceArrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia