P4172Prevalence and potential genetic determinants of young sudden unexplained death victims with suspected arrhythmogenic mitral valve prolapse

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Giudicessi ◽  
D Tester ◽  
M Ackerman
Keyword(s):  
Mitral Valve ◽  
Mitral Valve Prolapse ◽  
Molecular Mechanisms ◽  
Age At Death ◽  
Genetic Determinants ◽  
Contributing Factors ◽  
Benign Condition ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Whole Exome

Abstract Background Mitral valve prolapse (MVP) is largely considered a benign condition. Recently, arrhythmogenic MVP, a sudden cardiac death (SCD)-predisposing condition characterized clinically by frequent/complex ventricular arrhythmias likely secondary to prolapsing leaflet-induced fibrosis of the left ventricle (LV), has emerged as an underappreciated cause of sudden unexplained death in the young (SUDY). Objective To determine the prevalence and potential genetic underpinnings of suspected arrhythmogenic MVP in a referral cohort of SUDY cases. Methods In this retrospective necropsy study, the medical records, autopsy reports, and whole exome molecular autopsy (WEMA) results for 77 SUDY victims (27 females; average age at death 20.6±8.9 years) were reviewed. Evidence of myxomatous MVP and concomitant LV pathology were noted. Variants detected in the pre-specified 164 WEMA gene panel with a frequency <0.001 in public exomes were classified using the 2015 American College of Medical Genetics (ACMG) guidelines. Results Overall, 6/77 (7.8%; 2 females; average age at death 20.7±6.9 years) SUDY cases had MVP as the lone abnormal post-mortem finding. The majority had bileaflet involvement (5/6; 83%) and microscopic LV fibrosis (5/6; 83%). Two SUDY cases (33%) were diagnosed with MVP by echocardiography prior to death. No gross hypertrophy, myocyte disarray, or fibrofatty replacement was noted. Unexpectedly, an ACMG pathogenic/likely pathogenic (P/LP) was more likely to be detected in SUDY cases with MVP than those without [3/6 (50%) vs 9/71 (13%); p<0.05]. Interestingly, the three variants identified in MVP-positive SUDY cases localized to genes associated previously with a cardiomyopathy/channelopathy predisposition (p.E1518fsX25-DMD, p.S285N-RYR2, and p.R109X-TTN). Conclusion This WEMA series provides additional evidence that the combination of bileaflet MVP and microscopic LV fibrosis underlies an unexpected number of SUDY cases. Whether P/LP variants in cardiomyopathy/channelopathy-susceptibility genes function as contributing factors or if unrelated, but poorly understood, molecular mechanisms account for the distinct cardiomyopathy-like phenotype observed in arrhythmogenic MVP requires further investigation.

scholarly journals Malignant Arrhythmic Mitral Valve Prolapse: A Continuum of Clinical Challenges from Diagnosis to Risk Stratification and Patient Management

2020 ◽  
Vol 8 (1) ◽  
pp. 2
Author(s):  
Idit Yedidya ◽  
Aniek L. van Wijngaarden ◽  
Nina Ajmone Marsan
Keyword(s):  
Mitral Valve ◽  
Mitral Valve Prolapse ◽  
Ventricular Arrhythmias ◽  
Clinical Decision Making ◽  
Clinical Presentation ◽  
Clinical Decision ◽  
Benign Condition ◽  
Long Period ◽  
Patients Experience ◽  
Hospital Cardiac Arrest

Mitral valve prolapse (MVP) is a common valvular disease, which may remain a benign condition for a long period of time. However, some patients experience malignant ventricular arrhythmias and sudden cardiac death (SCD). It is still largely unknown how to risk-stratify these patients, and no specific recommendations have been proposed to help the clinical decision-making. We present the case of a young man whose first clinical presentation was an out-of-hospital cardiac arrest and was subsequently diagnosed with MVP. We highlighted the possible risk factors for SCD and the challenges in the clinical management of these patients.

Mitral Valve Prolapse and Athletic Participation in Children and Adolescents

PEDIATRICS ◽  
1995 ◽  
Vol 95 (5) ◽  
pp. 789-790
Author(s):  
Keyword(s):  
Mitral Valve ◽  
Children And Adolescents ◽  
Mitral Valve Prolapse ◽  
Holter Monitoring ◽  
Premature Ventricular Contractions ◽  
Benign Condition ◽  
Migraine Headaches ◽  
Asymptomatic Patients ◽  
Vascular Accidents

Mitral valve prolapse (MVP) is generally a benign condition characterized by the protrusion of the mitral valve leaflets into the left atrium during systole. The prevalence of MVP in individuals under the age of 18 years is estimated to be 5% but is higher in those with Marfan's syndrome and other collagen vascular disorders.1 A midsystolic nonejection click with or without a late systolic murmur is the auscultatory hallmark of this syndrome. The diagnosis of MVP in children and adolescents should be based primarily on auscultatory findings and not on minor echocardiographic findings.1 The prognosis in children and adolescents with isolated MVP appears to be excellent and complications are rare. In 553 children, aged 15 days to 18 years, who were involved in studies with a follow-up period of 6 to 9 years, the following were reported: subacute bacterial endocarditis (one case), cerebral vascular accidents (two cases), migraine headaches (four cases), and chest pain (12 cases).2,3 Only four cases of sudden death have been reported in patients younger than 20 years of age.1-4 In a study of 103 patients with MVP, 16% were found to have premature ventricular beats during exercise electrocardiography (ECG) (exercise test).3 Thirty-eight percent were found to have premature ventricular contractions (PVCs) on 24-hour ECG (Holter) monitoring. This study, however, does not report the true prevalence of dysrhythmias because all these subjects had been referred to a pediatric cardiologist for evaluation. It is likely that these reported numbers are high because asymptomatic patients are less often referred.

scholarly journals Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Elias L. Salfati ◽  
Emily G. Spencer ◽  
Sarah E. Topol ◽  
Evan D. Muse ◽  
Manuel Rueda ◽  
...  
Keyword(s):  
Sudden Death ◽  
Rare Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Molecular Diagnostic ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

scholarly journals Whole-Exome Molecular Autopsy After Exertion-Related Sudden Unexplained Death in the Young

2016 ◽  
Vol 9 (3) ◽  
pp. 259-265 ◽  
Author(s):  
Jason H. Anderson ◽  
David J. Tester ◽  
Melissa L. Will ◽  
Michael J. Ackerman
Keyword(s):  
Molecular Autopsy ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Whole Exome

Abstract 15841: Whole Exome Sequencing and Analysis for Sudden Unexplained Death in the Young: A Case Series

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nupoor Narula ◽  
David J Tester ◽  
Anna Paulmichl ◽  
Joseph J Maleszewski ◽  
Michael J Ackerman
Keyword(s):  
Sudden Death ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Effective Means ◽  
Susceptibility Gene ◽  
Case Series ◽  
Susceptibility Genes ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Whole Exome

Introduction: Annually, thousands of sudden deaths in individuals under the age of 35 years remain unexplained following a medico-legal autopsy and are termed autopsy negative sudden unexplained death in the young (SUDY). Cardiomyopathies, channelopathies, and metabolic disorders may underlie a significant number of SUDY cases. Previously, we demonstrated that 25% of autopsy-negative SUDY cases had mutations in the 4 major cardiac ion channel genes ( KCNQ1, KCNH2, SCN5A , and RYR2 ). However, over 100 sudden death-susceptibility genes have been discovered and may be implicated in SUDY. Objective: We explored the utility of whole exome sequencing (WES) followed by gene-specific surveillance as an efficient and effective means of performing post-mortem genetic testing in SUDY. Methods: Postmortem WES was performed on 14 consecutively-referred white SUDY victims (57% men; average age at death 17.4 ± 8.6 years) using the Agilent SureSelect Human All Exon V4+UTR capture kit and an Illumina HiSeq 2000 sequencer. Following variant alignment (hg19) and annotation, 117 cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes were surveyed to identify putative SUDY-associated mutations. Potentially pathogenic variants had to be non-synonymous and ultra-rare [i.e. absent in all 3 evaluated exome databases (1,000 Genome Project, the NHLBI GO Exome Sequencing Project, and Exome Chip Design)]. Results: On average, each SUDY case had 12,758 ± 2016 non-synonymous variants, of which 79 ± 15 localized to the 117 evaluated genes. Overall, 8 unique, ultra-rare variants (7 missense, 1 in-frame insertion) identified in 6 genes (3 in TTN ; 1 each in CACNA1C, JPH2, MYH7, VCL, RYR2 ) were detected in 7 of 14 cases (50%). Of the 7 missense alterations, 2 (T171M- CACNA1C , I22160T- TTN ) were predicted damaging by 3 in-silico tools. Conclusions: Although WES and gene-specific surveillance is an efficient and effective strategy to detect rare, potentially lethal, genetic variants, the accurate interpretation of each variant is daunting. Importantly, rarity, even ultra-rarity, does not equal pathogenicity even when the ultra-rare variant resides within a so-called sudden death-susceptibility gene.

Compound heterozygous KCNQ1 mutations (A300T/P535T) in a child with sudden unexplained death: Insights into possible molecular mechanisms based on protein modeling

Gene ◽  
2017 ◽  
Vol 627 ◽  
pp. 40-48 ◽  
Author(s):  
Erika Antúnez-Argüelles ◽  
Arturo Rojo-Domínguez ◽  
Ana Leticia Arregui-Mena ◽  
Leonor Jacobo-Albavera ◽  
Manlio Fabio Márquez ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Modeling ◽  
Compound Heterozygous ◽  
Sudden Unexplained Death ◽  
Unexplained Death

scholarly journals ARRHYTHMOGENESIS IN MITRAL VALVE PROLAPSE

2015 ◽  
Vol 22 (02) ◽  
pp. 227-234
Author(s):  
Muhammad Alamgir Khan ◽  
Syed Muhammad Imran Majeed ◽  
Faizania Shabbir ◽  
Tausif Ahmed Rajput
Keyword(s):  
Heart Rate ◽  
Heart Rate Variability ◽  
High Resolution ◽  
Mitral Valve ◽  
Mitral Valve Prolapse ◽  
Holter Monitoring ◽  
P Value ◽  
Late Potentials ◽  
Resting Heart Rate ◽  
Benign Condition

Mitral valve prolapse is generally considered a benign condition, however, asubset of patients remains at high risk of arrhythmogenesis which may lead to sudden cardiacdeath. Objective: To stratify risk of arrhythmogenesis in patients with mitral valve prolapseon the basis of high resolution ECG, Holter monitoring, resting heart rate and mitral leafletgeometry. Study Design: Cross sectional comparative study. Place of study: Armed ForcesInstitute of Cardiology (AFIC)/National Institute of Heart Diseases, Rawalpindi and Army MedicalCollege, Rawalpindi, Pakistan Methodology: Mitral leaflet displacement and thickness weremeasured on echocardiography in 37 patients with mitral valve prolapse. Resting heart rateand time domain indices of heart rate variability of each patient were recorded from 24 hoursHolter monitoring. High resolution ECG of all the patients was carried out to record ventricularlate potentials. Statistical analysis was performed using SPSS and the alpha value was set at<0.05 for significance. Results: The mean values for resting heart rate, leaflet displacement andleaflet thickness were 77.19±6.29 per minute, 3.64±0.92 mm and 4.96±0.79 mm respectively.Ventricular late potentials were present in 8 (21.62%) whereas heart rate variability was reducedin 5 (13.51%) patients. Leaflet thickness was significantly greater in patients with ventricularlate potentials as compared to those without (p-value 0.004). Patients with reduced heart ratevariability had significantly higher resting heart rate as compared to those with normal variability(p-value 0.02). One patient (2.7%) had ventricular late potentials, reduced heart rate variability,resting heat rate of 88 beats per minute and leaflet thickness over 5 mm. Conclusions:Combined effects of high resolution ECG, holter monitoring and leaflet geometry identified thehigh risk subset, comprising of 2.7% of the study population.

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