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 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.

Sudden cardiac death in the young: A qualitative study of experiences of family members with cardiogenetic evaluation.

Sudden cardiac death (SCD) is a devastating event for the family and the community, especially when it occurs in a young person (<45 years). Genetic heart diseases, including cardiomyopathies and primary arrhythmia syndromes, are an important cause of SCD in the young. Although cardiogenetic evaluation, that is, clinical evaluation, genetic testing, and psychological support, is increasingly performed after SCD, it is unknown how suddenly bereaved family members experience the process. We aimed to explore the experiences of family members with cardiogenetic evaluation after SCD, and their perception of the process and care received. In-depth interviews were conducted with 18 family members of young people (<45 years old) who died suddenly, including parents, siblings, and partners. The interviews were thematically analyzed by two researchers independently. In total, 18 interviews were conducted from 17 families. The following themes were identified: (1) Experiences with postmortem genetic testing including managing expectations and psychological impact, (2) appreciation of care such as access to genetic counseling and relief following cardiac evaluation of relatives, and (3) need for support including unmet psychological support needs and better coordination of care immediately after the death. Although participants appreciated the opportunity for cardiogenetic evaluation, they also experienced a lack of coordination of cardiogenetic and psychological care. Our findings stress the importance of access to expert multidisciplinary teams, including psychological care, to adequately support these families after a SCD in a young family member.

Longitudinal assessment of structural phenotype in Brugada syndrome using cardiac magnetic resonance imaging.

Background: Despite historically being considered a channelopathy, subtle structural changes have been reported in Brugada syndrome (BrS) on histopathology and cardiac magnetic resonance (CMR) imaging. It is not known if these structural changes progress over time. Objective: The study sought to assess if structural changes in BrS evolve over time with serial CMR assessment and to investigate the utility of parametric mapping techniques to identify diffuse fibrosis in BrS. Methods: Patients with a diagnosis of BrS based on international guidelines and normal CMR at least 3 years prior to the study period were invited to undergo repeat CMR. CMR images were analyzed de novo and compared at baseline and follow-up. Results: Eighteen patients with BrS (72% men; mean age at follow-up 47.4 ± 8.9 years) underwent serial CMR with an average of 5.0 ± 1.7 years between scans. No patients had late gadolinium enhancement (LGE) on baseline CMR, but 4 (22%) developed LGE on follow-up, typically localized to the right ventricular (RV) side of the basal septum. RV end-systolic volume increased over time (P = .04) and was associated with a trend toward reduction in RV ejection fraction (P = .07). Four patients showed a reduction in RV ejection fraction >10%. There was no evidence of diffuse myocardial fibrosis observed on parametric mapping. Conclusions: Structural changes may evolve over time with development of focal fibrosis, evidenced by LGE on CMR in a significant proportion of patients with BrS. These findings have implications for our understanding of the pathological substrate in BrS and the longitudinal evaluation of patients with BrS.

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Evaluating a communication aid for return of genetic results in families with hypertrophic cardiomyopathy: A randomized controlled trial.

Genetic testing for hypertrophic cardiomyopathy (HCM) is considered a key aspect of management. Communication of genetic test results to the proband and their family members, can be a barrier to effective uptake. We hypothesized that a communication aid would facilitate effective communication, and sought to evaluate knowledge and communication of HCM risk to at-risk relatives. This was a prospective randomized controlled trial. Consecutive HCM patients attending a specialized clinic, who agreed to participate, were randomized to the intervention or current clinical practice. The intervention consisted of a genetic counselor-led appointment, separate to their clinical cardiology review, and guided by a communication booklet which could be written in and taken home. Current clinical practice was defined as the return of the genetic result by a genetic counselor and cardiologist, often as part of a clinical cardiology review. The primary outcome was the ability and confidence of the individual to communicate genetic results to at-risk relatives. The a priori outcome of improved communication among HCM families did not show statistically significant differences between the control and intervention group, though the majority of probands in the intervention group achieved fair communication (n = 13/22) and had higher genetic knowledge scores than those in the control group (7 ± 3 versus 6 ± 3). A total of 29% of at-risk relatives were not informed of a genetic result in their family. Communication among HCM families remains challenging, with nearly a third of at-risk relatives not informed of a genetic result. We show a significant gap in the current approach to supporting family communication about genetics. Australian New Zealand Clinical Trials Registry: ACTRN12617000706370.

The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic.

BACKGROUND: The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and identify those with the highest likelihood of having a monogenic disease. METHODS: A retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020 was performed. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset, and severe phenotype, whereas low-scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated. RESULTS: A total of 888 probands fulfilled the inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 individuals (37%) and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15 to 20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing. CONCLUSIONS: Research-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease.

Concealed Cardiomyopathy in Autopsy-Inconclusive Cases of Sudden Cardiac Death and Implications for Families.

BACKGROUND: Genetic testing following sudden cardiac death (SCD) is currently guided by autopsy findings, despite the inherent challenges of autopsy examination and mounting evidence that malignant arrhythmia may occur before structural changes in inherited cardiomyopathy, so-called "concealed cardiomyopathy" (CCM). OBJECTIVES: The authors sought to identify the spectrum of genes implicated in autopsy-inconclusive SCD and describe the impact of identifying CCM on the ongoing care of SCD families. METHODS: Using a standardized framework for adjudication, autopsy-inconclusive SCD cases were identified as having a structurally normal heart or subdiagnostic findings of uncertain significance on autopsy. Genetic variants were classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. Family follow-up was performed where possible. RESULTS: Twenty disease-causing variants were identified among 91 autopsy-inconclusive SCD cases (mean age 25.4 ± 10.7 years) with a similar rate regardless of the presence or absence of subdiagnostic findings (25.5% vs 18.2%; P = 0.398). Cardiomyopathy-associated genes harbored 70% of clinically actionable variants and were overrepresented in cases with subdiagnostic structural changes at autopsy (79% vs 21%; P = 0.038). Six of the 20 disease-causing variants identified were in genes implicated in arrhythmogenic cardiomyopathy. Nearly two-thirds of genotype-positive relatives had an observable phenotype either at initial assessment or subsequent follow-up, and 27 genotype-negative first-degree relatives were released from ongoing screening. CONCLUSIONS: Phenotype-directed genetic testing following SCD risks under recognition of CCM. Comprehensive evaluation of the decedent should include assessment of genes implicated in cardiomyopathy in addition to primary arrhythmias to improve diagnosis of CCM and optimize care for families.

A prospective longitudinal study of health-related quality of life and psychological wellbeing after an implantable cardioverter-defibrillator in patients with genetic heart diseases.

Background: Genetic heart diseases (GHDs) can be clinically heterogeneous and pose an increased risk of sudden cardiac death (SCD). The implantable cardioverter-defibrillator (ICD) is a lifesaving therapy. Impacts on prospective and long-term psychological and health-related quality of life (HR-QoL) after ICD implant in patients with GHDs are unknown. Objectives: Investigate the psychological functioning and HR-QoL over time in patients with GHDs who receive an ICD, and identify risk factors for poor psychological functioning and HR-QoL. Methods: A longitudinal, prospective study design was used. Patients attending a specialized clinic, diagnosed with a GHD for which they received an ICD between May 2012 and January 2015, were eligible. Baseline surveys were completed prior to ICD implantation with 5-year follow-up after ICD implant. We measured psychological functioning (Hospital Anxiety Depression Scale, Florida Shock Anxiety Scale), HR-QoL (Short-Form 36v2), and device acceptance (Florida Patient Acceptance Scale). Results: Forty patients were included (mean age 46.3 ± 14.2 years; 65.0% male). Mean psychological and HR-QoL measures were within normative ranges during follow-up. After 12 months, 33.3% and 19.4% of participants showed clinically elevated levels of anxiety and depression, respectively. Longitudinal mixed-effect analysis showed significant improvements from baseline to first follow-up for the overall cohort, with variability increasing after 36 months. Nontertiary education and female sex predicted worse mental HR-QoL and anxiety over time, while comorbidities predicted depression and worse physical HR-QoL. Conclusion: While the majority of patients with a GHD adjust well to their ICD implant, a subset of patients experience poor psychological and HR-QoL outcomes.

Decision-making and experiences of preimplantation genetic diagnosis in inherited heart diseases: a qualitative study.

Preimplantation genetic diagnosis (PGD) ensures a disease-causing variant is not passed to the next generation, including for inherited heart diseases. PGD is known to cause significant emotional burden, but little is known about how parents experience PGD to select against inherited heart disease. We aim to understand how people with inherited heart disease, and their partners, experience and make decisions about PGD. Participants were recruited from a specialised inherited heart disease clinic. Qualitative semi-structured interviews were conducted with adult participants who had considered PGD. A semi-structured interview schedule explored overall experiences and reasons for undergoing PGD. Broad topics included experience of disease, reproductive history, psychosocial and financial considerations. Interviews were recorded, transcribed verbatim and thematically analysed using a framework method. Twenty participants were included (15 with inherited cardiomyopathy, 3 with inherited arrhythmia syndrome and 2 partners). In contemplating PGD, participants considered 3 main issues: past experience of disease e.g. sudden cardiac death, sport restrictions and clinical heterogeneity; intergenerational responsibilities; and practical considerations such as finances and maternal age. Among those who chose to undergo PGD (n = 7/18), past experience of a significant cardiac event, such as family history of sudden cardiac death, was important in the decision process. The decision to undergo PGD for inherited heart disease is complex and influenced by individual values and experience of disease. We highlight key areas where further discussion may assist in PGD decision processes.

Clinical Profile and Health Disparities in a Multiethnic Cohort of Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Clinical studies of hypertrophic cardiomyopathy are over-represented by individuals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population. METHODS: We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed. RESULTS: Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m2, P<0.0001). South Asians had a lower prevalence of atrial fibrillation (10% versus 31%, P=0.024). East Asians were more likely to have apical hypertrophy (23% versus 6%, P<0.0001) and Middle Eastern and North African patients more likely to present with left ventricular outflow tract obstruction (46% versus 34%, P=0.0003). East Asians were less likely to undergo genetic testing (55% versus 85%, P<0.0001) or have an implantable cardioverter-defibrillator implanted (19% versus 36%, P=0.037). East Asians were more likely to have a causative variant in a gene other than MYBPC3 or MYH7, whereas Middle Eastern and North African and South Asians had the highest rates of variants of uncertain significance (27% and 21%, P<0.0001). CONCLUSIONS: There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine-based care of individuals with hypertrophic cardiomyopathy.

Global approaches to cardiogenetic evaluation after sudden cardiac death in the young: A survey among health care professionals.

BACKGROUND: Thorough investigation of sudden cardiac death (SCD) in those aged 1-40 years commonly reveals a heritable cause, yet access to postmortem genetic testing is variable. OBJECTIVE: The purpose of this study was to explore practices of postmortem genetic testing and attitudes of health care professionals worldwide. METHODS: A survey was administered among health care professionals recruited through professional associations, social media, and networks of researchers. Topics included practices around postmortem genetic testing, level of confidence in health care professionals' ability, and attitudes toward postmortem genetic testing practices. RESULTS: There were 112 respondents, with 93% from North America, Europe, and Australia/New Zealand, and 7% from South America, Asia and Africa. Only 30% reported autopsy as mandatory, and overall practices were largely case by case and not standardized. North American respondents (87%) more often perceived practices as ineffective compared to those from Europe (58%) and Australia/New Zealand (48%; P = .002). Where a heritable cause is suspected, 69% considered postmortem genetic testing and 61% offered genetic counseling to surviving family members. Financial resources varied widely. Half of participants believed practices in their countries perpetuated health inequalities. CONCLUSION: Postmortem genetic testing is not consistently available in the investigation of young SCD despite being a recommendation in international guidelines. Access to postmortem genetic testing, which is critical in ascertaining a cause of death in many cases, must be guided by well-resourced, multidisciplinary teams.

"Concealed cardiomyopathy" as a cause of previously unexplained sudden cardiac arrest.

BACKGROUND: Genetic heart disease is a common cause of sudden cardiac arrest (SCA) in the young and those without an ischaemic precipitant. Identifying a cause of SCA in these patients allows for targeted care and family screening. Current guidelines recommend limited, phenotype-guided genetic testing in SCA survivors where a specific genetic condition is suspected and genetic testing is not recommended in clinically-idiopathic SCA survivors. OBJECTIVE: To investigate the diagnostic utility of broad, multi-phenotype genetic testing in clinically-idiopathic SCA survivors. METHODS: Clinically-idiopathic SCA survivors underwent analysis of genes known to be associated with either cardiomyopathy or primary arrhythmia syndromes, following referral to a specialised genetic heart disease clinic in Sydney, Australia between 1997 and 2019. Comprehensive review of clinical records, investigations and re-appraisal of genetic data according to current variant classification criteria was performed. RESULTS: In total, 22% (n = 8/36) of clinically-idiopathic SCA survivors (mean age 36.9 ± 16.9 years, 61% male) had a disease-causing variant identified on broad genetic testing. Of these, 7 (88%) variants resided in cardiomyopathy-associated genes (ACTN2, DES, DSP, MYBPC3, MYH7, PKP2) despite structurally normal hearts or sub-diagnostic structural changes at the time of arrest, so-called "concealed cardiomyopathy". Only one SCA survivor had a variant identified in a channelopathy associated gene (SCN5A). CONCLUSION: Extended molecular analysis with multi-phenotype genetic testing can identify a "concealed cardiomyopathy", and increase the diagnosis rate for clinically-idiopathic SCA survivors.

Ventricular Tachycardia in a Patient With Dilated Cardiomyopathy Caused by a Novel Mutation of Lamin A/C Gene: Insights From Features on Electroanatomic Mapping, Catheter Ablation and Tissue Pathology.

Lamin A/C (LMNA) cardiomyopathy forms an important and increasingly recognised group within the broad spectrum of non-ischaemic cardiomyopathies. LMNA cardiomyopathy typically presents with atrioventricular block followed by recurrent ventricular arrhythmias with a high tendency to progression to end stage heart failure. We present a case of recurrent ventricular tachycardia in a patient with dilated cardiomyopathy caused by a novel mutation of LMNA gene. Through electroanatomic mapping, catheter ablation and tissue pathology we provide detailed insights into this highly pathogenic inherited cardiomyopathy.

Genetic architecture of left ventricular noncompaction in adults.

The genetic etiology and heritability of left ventricular noncompaction (LVNC) in adults is unclear. This study sought to assess the value of genetic testing in adults with LVNC. Adults diagnosed with LVNC while undergoing screening in the context of a family history of cardiomyopathy were excluded. Clinical data for 35 unrelated patients diagnosed with LVNC at ≥18 years of age were retrospectively analyzed. Left ventricular (LV) dysfunction, electrocardiogram (ECG) abnormalities, cardiac malformations or syndromic features were identified in 25 patients; 10 patients had isolated LVNC in the absence of cardiac dysfunction or syndromic features. Exome sequencing was performed, and analysis using commercial panels targeted 193 nuclear and mitochondrial genes. Nucleotide variants in coding regions or in intron-exon boundaries with predicted impacts on splicing were assessed. Fifty-four rare variants were identified in 35 nuclear genes. Across all 35 LVNC patients, the clinically meaningful genetic diagnostic yield was 9% (3/35), with heterozygous likely pathogenic or pathogenic variants identified in the NKX2-5 and TBX5 genes encoding cardiac transcription factors. No pathogenic variants were identified in patients with isolated LVNC in the absence of cardiac dysfunction or syndromic features. In conclusion, the diagnostic yield of genetic testing in adult index patients with LVNC is low. Genetic testing is most beneficial in LVNC associated with other cardiac and syndromic features, in which it can facilitate correct diagnoses, and least useful in adults with only isolated LVNC without a family history. Cardiac transcription factors are important in the development of LVNC and should be included in genetic testing panels.

Needs analysis of parents following sudden cardiac death in the young.

OBJECTIVE: The sudden cardiac death (SCD) of a young person is a devastating event for any parent. Inherited heart disease is often either identified or assumed to be the cause. Few studies have explored the psychosocial impact to the surviving at-risk family members. We sought to investigate the needs of parents who have experienced the SCD of their child (≤45 years). METHODS: A quantitative needs analysis questionnaire was developed based on semistructured interviews, including one focus group and a review of relevant literature. Eligible participants were invited to participate in this cross-sectional survey study. RESULTS: There were 38 parents who completed a quantitative survey. Parents' perceived needs for information and support spanned medical, psychosocial, spiritual and financial domains. Of the support and information needs assessed, medical needs were identified as the most important domain, followed by psychosocial, spiritual and financial. Importantly, psychosocial information and support needs were reported as the most unmet need, endorsed by 54% of parents. Medical information and support needs were reported as unmet by almost one third of parents. The two most endorsed needs were 'To have the option of whether or not you would pursue genetic testing for yourself or family members' and 'To understand what happened'. CONCLUSIONS: This work demonstrates for the first time, the multifactorial needs of parents after SCD in the young. With the greatest unmet need reported as psychosocial needs, there is clear necessity to find ways of integrating psychological support in to the care of families after SCD in the young.

Prevalence of Anderson-Fabry disease in a cohort with unexplained late gadolinium enhancement on cardiac MRI.

INTRODUCTION: Fabry disease is a rare X-linked genetic disorder in which cardiac manifestations include LVH, contractile dysfunction, and fibrosis, visible on cardiac MRI (cMRI) as late gadolinium enhancement (LGE) of the myocardium. Fabry's disease is an important diagnosis to make as treatment is available as lifelong replacement of the deficient enzyme. AIM: To define the prevalence of Fabry disease in a cohort of patients with unexplained LGE on cMRI. METHODS: The study population was recruited from patients aged >16 years who had cMRI performed between 2010 and 2018 to investigate LVH, idiopathic LV dysfunction and/or idiopathic ventricular arrhythmia. Patients with 'unexplained' LGE i.e. without a genetic diagnosis of an alternate cardiomyopathy such as HCM or biopsy-proven infiltrative cardiomyopathy such as sarcoid or amyloid, were tested for Fabry disease by either genetic testing or the Dried Blood Spot test (Sanofi-Genzyme). RESULTS: Of the 79 patients with unexplained LGE on cMRI, 2 patients tested positive for Fabry disease, both using genetic sequencing techniques. The prevalence of Fabry disease in this selected cohort was 2.5%. Specifically, 1 patient was a 65 year old male and the other patient a 75 year old female. In both cases, the pattern and distribution of LGE on cMRI was of patchy mid-wall enhancement in the inferoseptum. CONCLUSION: Unexplained LGE on cMRI may be an isolated manifestation of late-onset Fabry disease. This finding should prompt testing for Fabry disease given this is a potentially treatable condition.

Perceptions of genetic variant reclassification in patients with inherited cardiac disease.

Interpretation of sequence variants is an ongoing challenge and new approaches aim to increase stringency. The reclassification of variants has the potential to alter medical management and elicit psychosocial consequences for patients. The perspective of patients with an inherited cardiac disease and a clinically significant variant reclassification was explored through semi-structured phone interviews. Participants were recruited from two specialized multidisciplinary centers in Canada and Australia. Qualitative analysis was performed through a thematic analysis approach. Fifteen participants were interviewed, including 9 (60%) with an inherited cardiomyopathy and 6 (40%) with an inherited arrhythmia syndrome. Six (40%) patients had a classification upgrade, while 9 (60%) had a downgrade. Four major themes emerged: (1) reactions towards the reclassified variant; (2) impact on decision-making; (3) perception of the reclassification process; and (4) improvement of the reclassification process. Many patients adjusted to the reclassification, however some misunderstood the implications, impacting their responses and decision-making. In conclusion, careful discussion with patients about uncertainty and the potential for reclassification are crucial to ensure a deeper understanding of the outcome of genetic testing and impact on families.