Impact of genetic tests on survivors of paediatric sudden cardiac arrest

ObjectiveTo retrospectively investigate the clinical spectrum, genetic profiles and outcomes of survivors of paediatric sudden cardiac arrest (SCA).Design and patientsAll 66 patients (aged 1–20 years), with unexpected SCA or syncope related to ventricular tachycardia (VT)/fibrillation and who survived to discharge from a tertiary centre, were enrolled from 1995 to 2018. Of these, 30 with underlying diseases prior to the events were excluded. Whole-exome sequencing targeting 384 channelopathy and cardiomyopathy-related genes (composite panel) was conducted to identify the possible genetic variants/mutations.ResultsA total of 36 patients were enrolled. Male adolescents predominated (66.7%), and the median age at onset was 13.3 years. Events occurred most often during exercise and daily activities. The yield rate of the genetic test was 84.6% (22/26); 14 had pathogenic variants; and 8 had likely pathogenic variants. The most common diagnoses were long QT in nine (25%), catecholaminergic polymorphic VT in six patients (16.7%), but other long QT and cardiomyopathy genes were also detected in eight patients (30.7%). The 10-year transplantation-free survival rate was 87.8% and was better for those who received genetic tests initially at the disease onset. An implantable cardioverter–defibrillator was implanted in 55.6% of the patients, with an appropriate shock rate of 61.1%. The defibrillator shock rate was lower for those who received composite panel initially.ConclusionSurvivors of SCA in the paediatric population had favourable long-term outcomes aided by genetic test. A broad composite genetic panel brings extra diagnostic value in the investigation of ventricular fibrillation/sudden cardiac death.

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Sudden Cardiac Arrest During Sex in Patients with Either Catecholaminergic Polymorphic Ventricular Tachycardia or Long-QT Syndrome: A Rare But Shocking Experience

Journal of Cardiovascular Electrophysiology ◽

10.1111/jce.12600 ◽

2015 ◽

Vol 26 (3) ◽

pp. 300-304 ◽

Cited By ~ 5

Author(s):

ROBERT W. LOAR ◽

J. MARTIJN BOS ◽

BRYAN C. CANNON ◽

MICHAEL J. ACKERMAN

Keyword(s):

Cardiac Arrest ◽

Ventricular Tachycardia ◽

Long Qt Syndrome ◽

Sudden Cardiac Arrest ◽

Catecholaminergic Polymorphic Ventricular Tachycardia ◽

Polymorphic Ventricular Tachycardia ◽

Long Qt ◽

Qt Syndrome

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Confirmation of Cause of Death Via Comprehensive Autopsy and Whole Exome Molecular Sequencing in People With Epilepsy and Sudden Unexpected Death

Journal of the American Heart Association ◽

10.1161/jaha.121.021170 ◽

2021 ◽

Cited By ~ 1

Author(s):

C. Anwar A. Chahal ◽

David J. Tester ◽

Ahmed U. Fayyaz ◽

Keerthi Jaliparthy ◽

Nadeem A. Khan ◽

...

Keyword(s):

Cardiac Arrest ◽

Sudden Death ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Cause Of Death ◽

Sudden Cardiac Arrest ◽

Sudden Unexpected Death ◽

Unexpected Death ◽

Pathogenic Variants ◽

Whole Exome

Background Sudden cardiac arrest is the leading mode of death in the United States. Epilepsy affects 1% of Americans; yet epidemiological data show a prevalence of 4% in cases of sudden cardiac arrest. Sudden unexpected death in epilepsy (SUDEP) may share features with sudden cardiac arrest. The objective of this study was to report autopsy and genomic findings in a large cohort of SUDEP cases. Methods and Results Mayo Clinic Sudden Death Registry containing cases (ages 0–90 years) of sudden unexpected and unexplained deaths 1960 to present was queried. Exome sequencing performed on decedent cases. From 13 687 cases of sudden death, 656 (4.8%) had a history of seizures, including 368 confirmed by electroencephalography, 96 classified as SUDEP, 58 as non‐SUDEP, and 214 as unknown (insufficient records). Mean age of death in SUDEP was 37 (±19.7) years; 56 (58.3%) were male; 65% of deaths occurred at night; 54% were found in bed; and 80.6% were prone. Autopsies were obtained in 83 cases; bystander coronary artery disease was frequently reported as cause of death; nonspecific fibrosis was seen in 32.6% of cases, in structurally normal hearts. There were 4 cases of Dravet syndrome with pathogenic variants in SCN1A gene. Using whole exome sequencing in 11 cases, 18 ultrarare nonsynonymous variants were identified in 6 cases including CACNB2, RYR2, CLNB, CACNA1H, and CLCN2 . Conclusions This study examined one of the largest single‐center US series of SUDEP cases. Several cases were reclassified as SUDEP, 15% had an ECG when alive, and 11 (11.4%) had blood for whole exome sequencing analysis. The most frequent antemortem genetic finding was pathogenic variants in SCN1A ; postmortem whole exome sequencing identified 18 ultrarare variants.

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Identification of pathogenic variants in genes related to channelopathy and cardiomyopathy in Korean sudden cardiac arrest survivors

Journal of Human Genetics ◽

10.1038/jhg.2017.8 ◽

2017 ◽

Vol 62 (6) ◽

pp. 615-620 ◽

Cited By ~ 3

Author(s):

Ju Sun Song ◽

Jong-Sun Kang ◽

Young-Eun Kim ◽

Seung-jung Park ◽

Kyoung-Min Park ◽

...

Keyword(s):

Cardiac Arrest ◽

Sudden Cardiac Arrest ◽

Pathogenic Variants

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Recurrent Torsade de Pointes During Mild Hypothermia Therapy for a Survivor of Sudden Cardiac Arrest Due to Drug-induced Long-QT Syndrome

Journal of Cardiovascular Electrophysiology ◽

10.1111/j.1540-8167.2009.01636.x ◽

2010 ◽

Vol 21 (4) ◽

pp. 462-463 ◽

Cited By ~ 3

Author(s):

TOMOHIRO MATSUHASHI ◽

TOSHIAKI SATO ◽

YOSHIYASU AIZAWA ◽

SEIJI TAKATSUKI

Keyword(s):

Cardiac Arrest ◽

Long Qt Syndrome ◽

Mild Hypothermia ◽

Sudden Cardiac Arrest ◽

Torsade De Pointes ◽

Long Qt ◽

Drug Induced ◽

Qt Syndrome

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Sudden cardiac arrest in a young adult with long QT syndrome and negative mutation studies

The Southwest Respiratory and Critical Care Chronicles ◽

10.12746/swrccc.v7i27.520 ◽

2019 ◽

Vol 7 (27) ◽

pp. 67-71

Author(s):

Walter Duarte ◽

Hawa Edriss

Keyword(s):

Cardiac Arrest ◽

Healthy Adult ◽

Serum Insulin ◽

Sudden Cardiac Arrest ◽

Insulin Level ◽

Temperature Management ◽

Long Qt ◽

Long Qt Interval ◽

Structural Abnormalities ◽

Peptide Level

Cardiac arrest in young healthy adults usually results from undiagnosed structural heartdisease or an undiagnosed predisposition to cardiac arrhythmias. We report a 19-year-old manwho developed a cardiac arrest while playing golf. He required cardiopulmonary resuscitationon 5 separate occasions and then was treated with targeted temperature management. Hisinitial laboratory tests included hypokalemia (2.5 mmol/L); he also had several episodes ofhypoglycemia during his intensive care unit stay. A serum insulin level was within normallimits, but a C-peptide level was increased. He had a long QT interval (QTc-551 ms) afterrewarming. Extensive cardiac workup was negative for structural abnormalities. In addition,mutation testing for channelopathies was negative. This patient recovered and has done well.This patient illustrates a case of sudden cardiac death in a young healthy adult who had a longQT syndrome but a negative mutation analysis. These patients might benefit from evaluationin specialized centers which can undertake additional genetic testing.

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Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

Circulation ◽

10.1161/circulationaha.115.015397 ◽

2015 ◽

Vol 131 (23) ◽

pp. 2051-2060 ◽

Cited By ~ 56

Author(s):

Helene M. Altmann ◽

David J. Tester ◽

Melissa L. Will ◽

Sumit Middha ◽

Jared M. Evans ◽

...

Keyword(s):

Cardiac Arrest ◽

Long Qt Syndrome ◽

Autosomal Recessive ◽

Sudden Cardiac Arrest ◽

Compound Heterozygous ◽

Long Qt ◽

Qt Syndrome

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“Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest

European Heart Journal ◽

10.1093/ehjci/ehaa946.0740 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J Isbister ◽

A Butters ◽

J Ingles ◽

R.W Sy ◽

R Bagnall ◽

...

Keyword(s):

Cardiac Arrest ◽

Genetic Testing ◽

Structural Changes ◽

Clinical Investigation ◽

Sudden Cardiac Arrest ◽

Specific Gene ◽

Funding Source ◽

Pathogenic Variants ◽

Cardiac Devices ◽

Actionable Variants

Abstract Background Current genetic testing guidelines recommend against broad, multi-phenotype genetic testing in survivors of sudden cardiac arrest (SCA) where no cause is identified on clinical screening. Recent reports describe malignant arrhythmic events preceding detectable structural changes in patients with pathogenic variants in cardiomyopathy genes, who go on to demonstrate structural changes in follow up. Purpose We sought to investigate the utility of a broad genetic testing approach, sequencing genes implicated in both arrhythmia syndromes and cardiomyopathy, in SCA survivors where no cause was identified after thorough clinical evaluation. Methods We retrospectively reviewed the clinical and genetic profiles of SCA survivors referred to a specialised genetic heart disease multidisciplinary team in Australia. Multi-phenotype genetic testing included analysis of 174 cardiac genes associated with arrhythmia or cardiomyopathy. Results The cohort was comprised of 86 SCA survivors. A clinical diagnosis was made in 46 (53%) patients while 40 (47%) cases were considered idiopathic, with no cause of arrest identified despite thorough clinical investigation. Thirty-two survivors of idiopathic SCA (80%) underwent broad, multi-phenotype genetic testing through genome (n=1), exome (n=26) or extended panel (n=5) analysis. The majority of the cohort were male (62.5%, n=25) and ≤35 years of age at time of arrest (60%, n=24). Events in this group most commonly occurred at rest or sleep (65.8%, n=25) and 5 patients had a family history of sudden death (12.5%). Seven disease causing variants were identified with a testing yield of 21.9%. There was no difference in demographic or clinical factors between those with and without a disease-causing variant. Six (85.7%) of these clinically actionable variants were identified in genes associated with cardiomyopathy (PKP2, MYBPC3, DES, DSP and ACTN2) that would not have been analysed on a standard commercial cardiac arrhythmia panel. Cardiac magnetic resonance (CMR) imaging was performed prior to genetic testing in 4 of the 6 cases found to have disease-causing variants in cardiomyopathy genes (2 patients did not have CMR performed due to the presence of cardiac devices), with 2 (50%) showing sub-diagnostic changes while 2 (50%) revealed a structurally normal heart. Conclusion A broad approach to genetic testing in idiopathic SCA can improve care for patients and their families by identifying clinically actionable variants that would be missed by phenotype specific gene panels and thus significantly increase the rate of diagnosis. “Concealed cardiomyopathy” represents a clinical challenge in how to manage patients and their relatives who carry a pathogenic cardiomyopathy variant, have no overt signs of structural disease, yet have an important risk of sudden cardiac arrest. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Cardiac Society of Australia and New Zealand; National Health and Medical Research Council (Australia)

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