The role of genetic testing in management and prognosis of individuals with inherited cardiomyopathies.

Inherited cardiomyopathies are a heterogeneous group of heart muscle conditions where disease classification has traditionally been based on clinical characteristics. However, this does not always align with genotype. While there are well described challenges of genetic testing, understanding the role of genotype in patient management is increasingly required. We take a gene-by-gene approach, reviewing current evidence for the role of genetic testing in guiding prognosis and management of individuals with inherited cardiomyopathies. In particular, focusing on confident variants in genes definitively associated with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy. This review identifies genotype-specific disease sub-groups with strong evidence supporting the use of genetics in clinical management and highlights that at present, the spectrum of clinical utility is not reflected in current guidelines. Of 13 guideline or expert consensus statements for management of cardiomyopathies, there are seven gene-specific therapeutic recommendations that have been published from four documents. Understanding how genotype influences phenotype provides evidence for the role of genetic testing for prognostic and therapeutic purposes, moving us closer to precision-medicine based care.

Multisite Validation of a Functional Assay to Adjudicate SCN5A Brugada Syndrome-Associated Variants.

BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification. METHODS: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was generated and independently studied at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function. RESULTS: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values yielded 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic. CONCLUSIONS: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.

A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers.

BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.

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.

Genetic testing in cardiovascular disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally and is responsible for an estimated one-third of deaths as well as significant morbidity and health care utilisation. Technological and bioinformatic advances have facilitated the discovery of pathogenic germline variants for some specific CVDs, including familial hypercholesterolaemia, cardiomyopathies and arrhythmic syndromes. Use of these genetic tests for earlier disease identification is increasing due, in part, to decreasing costs, Medicare rebates, and consumer comfort with genetic testing. However, CVDs that occur more commonly, including coronary artery disease and atrial fibrillation, do not display monogenic inheritance patterns. Genetically, these diseases have generally been associated with many genetic variants each with a small effect size. This complexity can be expressed mathematically as a polygenic risk score. Genetic testing kits that provide polygenic risk scoring are becoming increasingly available directly to private-paying consumers outside the traditional clinical setting. An improved understanding of the evidence of genetics in CVD will offer clinicians new opportunities for individualised risk prediction and preventive therapy.

Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.

Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z scores, the number of standard deviations from the mean of the normalized current density of the set of benign variant controls. A Z score of -2 defined the threshold for abnormal loss of function, which corresponds to 55% wild-type function. More extreme Z scores were observed for variants with a greater loss-of-function effect. We propose that the Z score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics variant classification framework. The validity of this approach was demonstrated using a series of 18 KCNH2 missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS) and the length of the corrected QT (QTc) interval.

Prevalence of atrial septal defects and patent foramen ovale in a cohort of sudden cardiac death patients undergoing autopsy.

BACKGROUND: Patent foramen ovale (PFO) and atrial septal defects (ASD) have been described in up to 30 % of subjects in autopsy series but contemporary data are scarce. It is important to confirm the prevalence of ASD/PFO in the general population given the potential associated stroke risk and the increasing availability of intervention via PFO closure. METHODS: A state-wide prospective out-of-hospital cardiac arrest registry (OHCA) identified all patients aged 1 to 50 years who experienced OHCA in Victoria, Australia from April 2019 to April 2022 and subsequently underwent autopsy with a cardiac cause of death identified. Autopsy was performed including visual description of any ASD and identification of probe patency of foramen ovale. RESULTS: A total of 517 patients underwent autopsy in the setting of sudden cardiac death; 36 patients (6.9 %) had a probe-patent foramen ovale, 2 patients (0.4 %) had secundum ASD, and 2 patients (0.4 %) had both a PFO and ASD (1 of whom had undergone percutaneous repair of both lesions). Twelve patients (2.3 %) had a prior history of cerebrovascular accident either recorded on medical history or detected on neuropathological examination; however none of these patients had a PFO or ASD. CONCLUSIONS: The combined rate of PFO and ASD in a cohort of 517 patients undergoing autopsy was 7.9 %. None of these patients had experienced a cerebrovascular accident. This rate of PFOs appears lower than earlier reports and raises the possibility that the relative risk of an associated stroke could be higher than previously estimated.

TBX20 loss-of-function variants in families with left ventricular non-compaction cardiomyopathy.

TBX20 encodes a cardiac transcription factor that is associated with atrial septal defects. Recent studies implicate loss-of-function TBX20 variants with left ventricular non-compaction cardiomyopathy (LVNC), although clinical and genetic data in families are limited. We report four families with TBX20 loss-of-function variants that segregate with LVNC. Genetic testing using genome or exome sequencing was performed in index cases, variants were validated with Sanger sequencing, and cascade genetic testing was performed in family members. A multi-exon deletion, small deletion, essential splice site variant and nonsense variant in TBX20 were found in four families. The index cases in two families were symptomatic children with identical congenital heart diseases and LVNC who developed different cardiomyopathy phenotypes with one developing heart failure requiring transplantation. In another family, the child index case had LVNC and congestive heart failure requiring heart transplantation. In the fourth family, the index case was a symptomatic adult with LVNC. In all families, the variants segregated in relatives with isolated LVNC, or with congenital heart disease or cardiomyopathy. Family members displayed a clinical spectrum from asymptomatic to severe presentations including heart failure. Our data strengthen TBX20 loss-of-function variants as a rare cause of LVNC and support TBX20 inclusion in genetic testing of LVNC.

A case series of patients with filamin-C truncating variants attending a specialized cardiac genetic clinic.

Background: FLNC encodes for filamin-C, a protein expressed in Z-discs of cardiac and skeletal muscle, involved in intracellular signalling and mechanical stabilization. Variants can cause diverse phenotypes with skeletal (myofibrillar or distal myopathy) and/or cardiac (hypertrophic, restrictive, and arrhythmogenic cardiomyopathies) manifestations. Truncating variants have recently been implicated in arrhythmogenic cardiomyopathy (ACM) without skeletal disease. Case summary: Retrospective review of medical records, including cardiac investigations, was performed for families attending a specialized clinic with a FLNC truncating variant (FLNCtv). Variants were classified according to accepted variant interpretation criteria. Of seven families identified, six had primary cardiac phenotypes with one nonsense and five frameshift variants (nonsense-mediated decay competent) identified. One family had no cardiac phenotype, with a pathogenic variant (p.Arg2467Alafs*62) identified as secondary genetic finding. Of the six with cardiac phenotypes, proband age at diagnosis ranged 27-35 years (four females). Five families experienced sudden cardiac death (SCD) of a young relative (age range: 30-43 years), and one patient listed for cardiac transplant. Left ventricular (LV) ejection fraction ranged from 13 to 46%, with LV fibrosis (late gadolinium enhancement) on cardiac imaging or on postmortem histology seen in three families. Two families had one genotype-positive/phenotype-negative relative. Discussion: The FLNCtv causes a left-sided ACM phenotype with a high risk of severe cardiac outcomes including end-stage heart failure and SCD. Incomplete penetrance is observed with implications for reporting secondary genetic findings.

Prevalence of Multiple Causes of Death Within Young and Middle-Aged People Experiencing Sudden Cardiac Arrest.

BACKGROUND: Multiple causes of death are increasingly reported, particularly in older populations. Rates of multiple causes of young sudden death have not been quantified. METHOD: The End Unexplained Cardiac Death (EndUCD) registry was utilised to identify cases of young sudden death (aged 1-50 years) referred for forensic assessment from April 2019 to April 2022. Causes of death were coded according to whether one or more underlying causes of death were identified. Patients were compared according to the number of causes of death, with significant predictors assessed using logistic regression analysis. RESULTS: 1,085 cases of sudden death were identified. 263 (24.2%) cases had more than one competing cause of their sudden death. The most common multi-causal associations identified were dual non-cardiac causes of the sudden death (n=68), cardiomyopathy with non-cardiac event (n=64) and coronary artery disease with non-cardiac cause (n=63). Multi-causal death was more common in those undergoing comprehensive autopsy examination (95.8% vs 77.6%, p<0.0001), and in the setting of higher body mass index (median 31.3 kg/m2 vs 29.9 kg/m2, p=0.01), older age (44.3 years vs 41.4 years, p<0.0001), non-ventricular cardiac arrest rhythm (93.2% vs 87.3%, p=0.009), and smoking (22.8% vs 14.2%, p=0.001). The strongest predictor of multiple pathologies was comprehensive autopsy examination compared with external inspection, full-body post-mortem computed tomography and review of ancillary documentation and investigations (odds ratio 6.49, 95% confidence interval 3.47-12.14). CONCLUSIONS: One-quarter of young sudden deaths have more than one underlying cause, highlighting the value of comprehensive investigations including autopsy. Awareness of the complexity of young sudden death is important, along with multidisciplinary involvement to ensure all contributors to death are identified.

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.

The burden of splice-disrupting variants in inherited heart disease and unexplained sudden cardiac death.

There is an incomplete understanding of the burden of splice-disrupting variants in definitively associated inherited heart disease genes and whether these genes can amplify from blood RNA to support functional confirmation of splicing outcomes. We performed burden testing of rare splice-disrupting variants in people with inherited heart disease and sudden unexplained death compared to 125,748 population controls. ClinGen definitively disease-associated inherited heart disease genes were amplified using RNA extracted from fresh blood, derived cardiomyocytes, and myectomy tissue. Variants were functionally assessed and classified for pathogenicity. We found 88 in silico-predicted splice-disrupting variants in 128 out of 1242 (10.3%) unrelated participants. There was an excess burden of splice-disrupting variants in PKP2 (5.9%), FLNC (2.7%), TTN (2.8%), MYBPC3 (8.2%) and MYH7 (1.3%), in distinct cardiomyopathy subtypes, and KCNQ1 (3.6%) in long QT syndrome. Blood RNA supported the amplification of 21 out of 31 definitive disease-associated inherited heart disease genes. Our functional studies confirmed altered splicing in six variants. Eleven variants of uncertain significance were reclassified as likely pathogenic based on functional studies and six were used for cascade genetic testing in 12 family members. Our study highlights that splice-disrupting variants are a significant cause of inherited heart disease, and that analysis of blood RNA confirms splicing outcomes and supports variant pathogenicity classification.

The Australian Genetic Heart Disease Registry: Protocol for a Data Linkage Study.

BACKGROUND: Genetic heart diseases such as hypertrophic cardiomyopathy can cause significant morbidity and mortality, ranging from syncope, chest pain, and palpitations to heart failure and sudden cardiac death. These diseases are inherited in an autosomal dominant fashion, meaning family members of affected individuals have a 1 in 2 chance of also inheriting the disease ("at-risk relatives"). The health care use patterns of individuals with a genetic heart disease, including emergency department presentations and hospital admissions, are poorly understood. By linking genetic heart disease registry data to routinely collected health data, we aim to provide a more comprehensive clinical data set to examine the burden of disease on individuals, families, and health care systems. OBJECTIVE: The objective of this study is to link the Australian Genetic Heart Disease (AGHD) Registry with routinely collected whole-population health data sets to investigate the health care use of individuals with a genetic heart disease and their at-risk relatives. This linked data set will allow for the investigation of differences in outcomes and health care use due to disease, sex, socioeconomic status, and other factors. METHODS: The AGHD Registry is a nationwide data set that began in 2007 and aims to recruit individuals with a genetic heart disease and their family members. In this study, demographic, clinical, and genetic data (available from 2007 to 2019) for AGHD Registry participants and at-risk relatives residing in New South Wales (NSW), Australia, were linked to routinely collected health data. These data included NSW-based data sets covering hospitalizations (2001-2019), emergency department presentations (2005-2019), and both state-wide and national mortality registries (2007-2019). The linkage was performed by the Centre for Health Record Linkage. Investigations stratifying by diagnosis, age, sex, socioeconomic status, and gene status will be undertaken and reported using descriptive statistics. RESULTS: NSW AGHD Registry participants were linked to routinely collected health data sets using probabilistic matching (November 2019). Of 1720 AGHD Registry participants, 1384 had linkages with 11,610 hospital records, 7032 emergency department records, and 60 death records. Data assessment and harmonization were performed, and descriptive data analysis is underway. CONCLUSIONS: We intend to provide insights into the health care use patterns of individuals with a genetic heart disease and their at-risk relatives, including frequency of hospital admissions and differences due to factors such as disease, sex, and socioeconomic status. Identifying disparities and potential barriers to care may highlight specific health care needs (eg, between sexes) and factors impacting health care access and use. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48636.

The Lancet Commission to reduce the global burden of sudden cardiac death: a call for multidisciplinary action.

Despite major advancements in cardiovascular medicine, sudden cardiac death (SCD) continues to be an enormous medical and societal challenge, claiming millions of lives every year. Efforts to prevent SCD are hampered by imperfect risk prediction and inadequate solutions to specifically address arrhythmogenesis. Although resuscitation strategies have witnessed substantial evolution, there is a need to strengthen the organisation of community interventions and emergency medical systems across varied locations and health-care structures. With all the technological and medical advances of the 21st century, the fact that survival from sudden cardiac arrest (SCA) remains lower than 10% in most parts of the world is unacceptable. Recognising this urgent need, the Lancet Commission on SCD was constituted, bringing together 30 international experts in varied disciplines. Consistent progress in tackling SCD will require a completely revamped approach to SCD prevention, with wide-sweeping policy changes that will empower the development of both governmental and community-based programmes to maximise survival from SCA, and to comprehensively attend to survivors and decedents' families after the event. International collaborative efforts that maximally leverage and connect the expertise of various research organisations will need to be prioritised to properly address identified gaps. The Commission places substantial emphasis on the need to develop a multidisciplinary strategy that encompasses all aspects of SCD prevention and treatment. The Commission provides a critical assessment of the current scientific efforts in the field, and puts forth key recommendations to challenge, activate, and intensify efforts by both the scientific and global community with new directions, research, and innovation to reduce the burden of SCD worldwide.

Sudden Cardiac Death in People With Schizophrenia: Higher Risk, Poorer Resuscitation Profiles, and Differing Pathologies.

BACKGROUND: People with schizophrenia account for approximately 1.0% of the population and seem to experience increased rates of sudden cardiac death (SCD). OBJECTIVES: This study sought to determine characteristics of increased SCD in people with schizophrenia. METHODS: The End Unexplained Cardiac Death (EndUCD) prospective state-wide registry compared people aged 15 to 50 years with and without schizophrenia who experienced SCD within a 2-year time period and were referred for forensic evaluation. RESULTS: We identified 579 individuals, of whom 65 (11.2%) had schizophrenia. Patients with schizophrenia were more commonly smokers (46.2% vs 23.0%; P < 0.0001), consumed excess alcohol (32.3% vs 21.4%; P = 0.05), and used QTc-prolonging medications (69.2% vs 17.9%; P < 0.0001). They were less likely to arrest while exercising (0.0% vs 6.4%; P = 0.04). Unfavorable arrest-related factors included lower rates of witnessed arrest (6.2% vs 23.5%; P < 0.0001), more likely to be found in asystole (92.3% vs 73.3%; P < 0.0001), and being more likely to be found as part of a welfare check after a prolonged period of time (median 42 hours vs 12 hours; P = 0.003). There was more frequent evidence of decomposition, and they more commonly underwent autopsy (41.2% vs 26.4%; P = 0.04 and 93.8% vs 82.5%; P = 0.05), with a diagnosis of nonischemic cardiomyopathy being more common (29.2% vs 18.1%; P = 0.04). CONCLUSIONS: People with schizophrenia account for 11% of young SCD patients referred for forensic investigations, exceeding population rates by 11-fold. They have a higher preexisting cardiac risk factor burden, unfavorable resuscitation profiles, and higher rates of nonischemic cardiomyopathy. Strategies targeting biopsychosocial support may deliver not only psychological benefits, but also help to decrease unwitnessed cardiac arrest.

The New South Wales Sudden Cardiac Arrest Registry: A Data Linkage Cohort Study.

BACKGROUND: Sudden cardiac arrest (SCA) in young people aged 1 to 50 years often occurs with no presenting symptoms or risk factors prompting screening for cardiovascular disease prior to their cardiac arrest. Approximately 3,000 young Australians suffer from sudden cardiac death (SCD) each year, making this a major public health issue. However, there is significant variation in the way incidence is estimated resulting in discrepancy across reporting which impacts our ability to understand and prevent these devastating events. We describe the New South Wales (NSW) Sudden Cardiac Arrest Registry: a retrospective, data linkage study which will identify all SCAs in the young in NSW from 2009 through to June 2022. OBJECTIVE: To determine the incidence, demographic characteristics and causes of SCA in young people. We will develop an NSW-based registry that will contribute to a greater understanding of SCA including risk factors and outcomes. METHODS: The cohort will include all people who experience a SCA in the NSW community aged between 1 to 50 years. Cases will be identified using the following three datasets: the Out of Hospital Cardiac Arrest Register housed at NSW Ambulance, the NSW Emergency Department Data Collection, and the National Coronial Information System. Data from eight datasets will be collected, anonymised and linked for the entire cohort. Analysis will be undertaken and reported using descriptive statistics. CONCLUSIONS: The NSW SCA registry will be an important resource for the improved understanding of SCA and inform the widespread impacts it has on individuals, their families and society.