scholarly journals 118 Undefined left ventricular arrhythmogenic cardiomyopathy: the value of genotyping and histological characterization

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Giovanni Peretto ◽  
Michela Casella ◽  
Marco Merlo ◽  
Stefania Rizzo ◽  
Chiara Cappelletto ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Left Ventricular ◽  
Study Endpoint ◽  
Myocardial Inflammation ◽  
Study Cohort ◽  
Arrhythmogenic Cardiomyopathy ◽  
Prognostic Assessment ◽  
Pathogenic Variants ◽  
Classification Management ◽  
Next Generation Sequencing Ngs

Abstract Aims Etiology identification and risk stratification represent major issues for patients presenting with undefined left ventricular arrhythmogenic cardiomyopathy (ULVACM). To investigate the role of genotyping and histology for ULVACM classification, management, and risk assessment. Methods and results We retrospectively analysed a multicentre cohort of patients (screened n = 1037) with ULVACM defined by ventricular arrhythmia (VA) onset, nonischaemic late gadolinium enhancement (LGE) limited to the LV, and no manifest dilated cardiomyopathy (LVEF ≥ 40%). We selected patients undergoing both next generation sequencing (NGS) genotyping and endomyocardial biopsy (EMB) for etiology definition. When feasible, immunosuppressive therapy (IST) was used to target active myocardial inflammation (AMI). The study endpoint was a composite of cardiac death, heart transplantation and malignant VAs (VT, VF, appropriate ICD treatment). The study cohort is composed by 135 ULVACM patients (age 43 ± 14 years, 63% males, LVEF 55 ± 7%). NGS identified pathogenic or likely-pathogenic variants (PVs/LPVs) consistent with ACM in 21 cases (16%), whereas EMB showed AMI in 78 patients (58%), including 13/21 PVs/LPVs + (62%). IST was started in 41/78 AMI patients (53%), including 9/13 PVs/LPVs + (69%). Twenty patients (15%) met the study endpoint by 12 months, and 36 (27%) by the end of the study (60 ± 27 months). Beyond malignant VT onset, AMI was the only predictor of events by 12 months (HR: 5.0, 95% CI: 1.4–18.1, P = 0.007). No prognostic role was found for PVs/LPVs, except for the subgroup (n = 77) with nonsustained VT onset. Among AMI patients, those treated by IST had a significantly lower occurrence of events, both by 12-months (1/41 vs. 16/37, P < 0.001) and later (HR: 0.05, 95% CI: 0.01–0.21, P < 0.001). Results were independently confirmed in PVs/LPVs+ and PVs/LPVs- cases. Excluding the IST population, the association of multiple factors among VT onset, PVs/LPVs, and AMI, resulted in an improved discrimination of arrhythmic risk profiles. Conclusions Despite its limited diagnostic yield, the combined genetic and histological workup substantially contributed into ULVACM prognostic assessment. Furthermore, EMB identified suitable candidates for IST, who showed better outcomes irrespectively of their genotype.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2021 ◽  
Author(s):  
Stephen E. Lincoln ◽  
Tina Hambuch ◽  
Justin M. Zook ◽  
Sara L. Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
Next Generation Sequencing Ngs ◽  
The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

scholarly journals Progressive Myoclonus Epilepsies

2021 ◽  
Vol 7 (6) ◽  
pp. e641
Author(s):  
Laura Canafoglia ◽  
Silvana Franceschetti ◽  
Antonio Gambardella ◽  
Pasquale Striano ◽  
Anna Teresa Giallonardo ◽  
...  
Keyword(s):  
Late Onset ◽  
Diagnostic Yield ◽  
Homozygosity Mapping ◽  
Genetic Origin ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Progressive Ataxia ◽  
Targeted Ngs ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

scholarly journals Is galectin-3 a promoter of ventricular dysfunction?

2018 ◽  
Vol 26 (1) ◽  
pp. 21-36
Author(s):  
Adrian Lupu ◽  
Silvia Lupu ◽  
Lucia Agoston-Coldea
Keyword(s):  
Heart Failure ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Left Ventricular ◽  
Myocardial Inflammation ◽  
Clinical Settings ◽  
Comprehensive Overview ◽  
Prognostic Assessment ◽  
Patients With Heart Failure ◽  
Galectin 3

Abstract Heart failure is nowadays a common condition associated with high mortality and increased healthcare-related costs. Over the years, the research on heart failure management has been extensive in order to better diagnose and treat the condition. Since the progression of left ventricular dysfunction is a consequence of myocardial inflammation, apopotosis, and fibrosis leading to myocardium remodelling, several molecules that are involved in the inflammation pathways have been explored as possible biomarkers for the condition. The study of biomarkers and their key roles in inflammation could allow early identification of patients with heart failure, improve prognostic assessment, and provide a target for future therapies. Among currently studied biomarkers, extensive research has been conducted on galectin-3, a galactoside-binding lectin, which is synthetised and secreted when cardiomyocytes and fibroblasts are submitted to mechanical stress. Accordingly, it has been hypothesised that galectin-3 could be a promoter of left ventricular dysfunction. Galectin-3 has been shown to mediate inflammation by several different pathways which are further detailed in the current review. Also, we aimed to provide a comprehensive overview of existing evidence on the utility of galectin-3 in clinical settings associated with heart failure.

scholarly journals Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance

2021 ◽  
Vol 10 (9) ◽  
pp. 1806
Author(s):  
Mercedes Iglesias ◽  
Tomas Ripoll-Vera ◽  
Consuelo Perez-Luengo ◽  
Ana Belen García ◽  
Susana Moyano ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Ventricular Hypertrophy ◽  
Diagnostic Yield ◽  
Left Ventricular ◽  
Molecular Autopsy ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Uncertain Significance ◽  
Frequent Variant

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.

scholarly journals Genetic architecture of left ventricular noncompaction in adults

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Samantha Barratt Ross ◽  
Emma S. Singer ◽  
Elizabeth Driscoll ◽  
Natalie Nowak ◽  
Laura Yeates ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Genetic Testing ◽  
Family History ◽  
Cardiac Dysfunction ◽  
Diagnostic Yield ◽  
Left Ventricular ◽  
Left Ventricular Noncompaction ◽  
Ventricular Noncompaction ◽  
Pathogenic Variants ◽  
Cardiac Transcription Factors

AbstractThe 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.

scholarly journals B-PO02-124 NONISCHEMIC LEFT VENTRICULAR CARDIOMYOPATHY WITH PRESERVED LEFT VENTRICULAR FUNCTION: A TYPE OF ARRHYTHMOGENIC CARDIOMYOPATHY

Heart Rhythm ◽  
2021 ◽  
Vol 18 (8) ◽  
pp. S148
Author(s):  
Ikutaro Nakajima ◽  
Kenichi Tokutake ◽  
Asad A. Aboud ◽  
Oluwaseun Adeola ◽  
Travis D. Richardson ◽  
...  
Keyword(s):  
Left Ventricular Function ◽  
Ventricular Function ◽  
Left Ventricular ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy

scholarly journals Cardiomyopathies: An Overview

2021 ◽  
Vol 22 (14) ◽  
pp. 7722
Author(s):  
Tiziana Ciarambino ◽  
Giovanni Menna ◽  
Gennaro Sansone ◽  
Mauro Giordano
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Dilated Cardiomyopathy ◽  
Sudden Cardiac Arrest ◽  
Restrictive Cardiomyopathy ◽  
The United States ◽  
Abrupt Onset ◽  
Left Ventricular ◽  
Arrhythmogenic Cardiomyopathy ◽  
Athletic Field ◽  
Fibrofatty Tissue

Background: Cardiomyopathies are a heterogeneous group of pathologies characterized by structural and functional alterations of the heart. Aims: The purpose of this narrative review is to focus on the most important cardiomyopathies and their epidemiology, diagnosis, and management. Methods: Clinical trials were identified by Pubmed until 30 March 2021. The search keywords were “cardiomyopathies, sudden cardiac arrest, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy, arrhythmogenic cardiomyopathy (ARCV), takotsubo syndrome”. Results: Hypertrophic cardiomyopathy (HCM) is the most common primary cardiomyopathy, with a prevalence of 1:500 persons. Dilated cardiomyopathy (DCM) has a prevalence of 1:2500 and is the leading indication for heart transplantation. Restrictive cardiomyopathy (RCM) is the least common of the major cardiomyopathies, representing 2% to 5% of cases. Arrhythmogenic cardiomyopathy (ARCV) is a pathology characterized by the substitution of the myocardium by fibrofatty tissue. Takotsubo cardiomyopathy is defined as an abrupt onset of left ventricular dysfunction in response to severe emotional or physiologic stress. Conclusion: In particular, it has been reported that HCM is the most important cause of sudden death on the athletic field in the United States. It is needless to say how important it is to know which changes in the heart due to physical activity are normal, and when they are pathological.

scholarly journals Sustained ventricular tachycardia of left, right or both bundle branch block morphology in patients with Arrhythmogenic Cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Milman ◽  
M Laredo ◽  
R Roudijk ◽  
G Peretto ◽  
A Andorin ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Right Bundle Branch Block ◽  
Left Bundle Branch Block ◽  
Clinical Course ◽  
Left Ventricular ◽  
Funding Source ◽  
Arrhythmogenic Cardiomyopathy ◽  
Icd Implantation ◽  
Bundle Branch Block ◽  
Group 3

Abstract Aims In arrhythmogenic cardiomyopathy (ACM) sustained monomorphic ventricular tachycardia (VT) typically displays left bundle branch block (LBBB) morphology. Sustained VT with right bundle branch block (RBBB) morphology is very rare despite the frequent left ventricular involvement. The present study sought to assess the prevalence of spontaneous sustained LBBB-VT, RBBB-VT or both as well as clinical and genetic differences associated with these VT types. Methods and results Twenty-six centers from 11 European countries provided information on 952 patients with ACM and >1 episode of sustained VT observed during the patients' clinical course. VT was classified as: LBBB-VT; RBBB-VT or LBBB+RBBB-VT. Among 952 patients, 881 (92.5%) had LBBB-VT alone, 71 (7.5%) had RBBB-VT [alone in 42 (4.4%) patients or with LBBB-VT in 29 (3.0%) patients]. Male prevalence was 90.5%, 79.2% and 55.9% in the RBBB-VT, LBBB-VT and LBBB+RBBB-VT groups, respectively (P=0.001). Patients' age at first VT did not differ amongst the 3 VT groups. ICD implantation was more frequent for the RBBB-VT and the LBBB+RBBB groups (≈90% each) vs. 67.9% for the LBBB-VT group (P=0.001). Death incidence (9.5%–17.2%) was not significantly different between the 3 groups (P=0.425). Plakophylin-2 mutations predominated in the LBBB-VT and LBBB-VT+RBBB-VT groups (47.2% and 27.3%, respectively) and Desmoplakin mutations in the RBBB-VT group (36.7%). Conclusion This large European survey demonstrates: 1) Sustained RBBB-VT is documented in 7.5% patients with ACM; 2) Males markedly predominate in the RBBB-VT and LBBB-VT groups but not in the LBBB+RBBB VT group; 3) Distribution of desmosomal mutations appears to be different in the 3 VT groups. Funding Acknowledgement Type of funding source: None

The role of inflammation in recent-onset dilated cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Chaloupka ◽  
J Krejci ◽  
H Poloczkova ◽  
P Hude ◽  
E Ozabalova ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Left Ventricular ◽  
Pcr Analysis ◽  
Myocardial Inflammation ◽  
Gene Variants ◽  
Absolute Increase ◽  
Recent Onset ◽  
Cardiotropic Viruses

Abstract Background The aetiology of recent-onset dilated cardiomyopathy (RODCM) includes inflammatory, genetic, toxic and metabolic causes. Delineating the role of inflammation on the genetic background could improve risk stratification. Purpose We aimed to ascertain the role of inflammation evaluated by serum CRP immunohistochemical and PCR analysis of endomyocardial biopsy (EMB) in conjunction with genetic testing in left ventricular reverse remodelling (LVRR) in 12-month follow-up. Methods 83 RODCM patients enrolled in this prospective observational study underwent 12-month echocardiographic follow up whole-exome sequencing, and EMB. Presence of cardiotropic viruses was determined by PCR analysis of the EMB samples. Inflammation was defined according to TIMIC immunohistochemical criteria as the presence of >7 CD3+ lymphocytes/mm2 and/or >14 infiltrating leukocytes (LCA+ cells/mm2). LVRR was defined as an absolute increase in LV ejection fraction > +10% and a relative decrease of LV end-diastolic diameter >−10% at 12 months. Results LVRR occurred in 28 (34%) of all cases. PCR analysis uncovered cardiotropic viruses in 55 (66%) patients, with highest prevalence of parvovirus B19 (47%). (Figure 1) EMB analysis detected inflammation in 28 (34%) cases and inflammation significantly positively predicted LVRR (P=0.019). Sequencing identified disease-related gene variants (ACMG class 3–5) in 45 (54%) patients. Carriers of non-titin gene variants showed a lowest probability of 12-month LVRR (19%) P=0.041. Combination of genetic findings and inflammation did not improve the prediction of LVRR in 12 months. (Table 1) Conclusion Both myocardial inflammation and disease-causing variants can be identified in a large proportion of RODCM cases. Prognostic value of CRP and virus detection is low. Non-titin disease-related variants carriers of are less likely to reach LVRR. In contrast, myocardial inflammation detected by EMB predicts favourable remodelling in 12 months. Figure 1 Funding Acknowledgement Type of funding source: None

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