The role of genetics in inherited cardiomyopathies

While the role of genetics in inherited cardiomyopathies has been recognised as a diagnostic tool for decades, utility of genetics as a prognostic and/or therapeutic tool is relatively new. This thesis takes a gene-specific approach to demonstrate the role genetics can play beyond diagnosis and family screening, and demonstrates gaps and limitations of our knowledge at present in this highly dynamic field. A review of the utility of genetics in diagnosis, prognosis, and clinical management in inherited cardiomyopathies was conducted. This identified genotype-specific disease sub-groups with strong evidence supporting the use of genetics in clinical management and highlighting that at present the spectrum of clinical utility is not reflected in current guidelines. A case series of FLNC truncating variants is presented and confirms a distinct left-sided arrhythmogenic cardiomyopathy phenotype with high risk of severe cardiac outcomes including end-stage heart failure and sudden cardiac death. This presents an exciting example of insights that can be gleaned from better understanding genotype-specific disease sub-groups, with benefit for patient management and outcomes. A cohort of patients with heterozygous ALPK3 loss-of-function variants is described and highlights potential issues that should be considered before this mechanism is definitively associated as a monogenic cause of hypertrophic cardiomyopathy. This includes variable expression with potential for considerable incomplete penetrance, as well as challenges identified due to transcript evolution and correction. Classification of inherited cardiomyopathies to specific gene and variant type is increasing the value of genetic testing beyond family screening and quickly becoming an important tool in improving diagnosis and management of patients. Although, there are significant gaps in current knowledge which need to be addressed, and limitations due to the rapidly evolving nature of the field

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

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

Background and Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic car-Aims diomyopathy 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

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

Abstract 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

ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes. Methods: The ClinGen systematic gene curation framework was used to re-classify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was &gt;2-3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD-GCEP composed of 29 individuals from 21 institutions across 6 countries. Results: Thirty-one genes were re-curated and an additional 5 new potential HCM-associated genes were curated. Among the re-curated genes, 17 (55%) genes changed classification: 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns (TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semi-dominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive). Conclusions: We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions.</jats:p