An observational study in Tachycardia, sponsored by University of Sao Paulo. Recruiting at 1 site in Brazil. Open to participants aged 5 Years to 50 Years. Per ClinicalTrials.gov, last updated 2026-10-05.
Sponsored by University of Sao Paulo · Observational
The goal of this observational study is to create and test a pilot workflow for molecular autopsy (genetic testing after death) in children and adults aged 1 to 50 years who died suddenly from an unexplained cause and were examined at the Death Verification Service of the city of São Paulo, Brazil.
The main questions it aims to answer are:
Sudden cardiac death in young people is often caused by inherited heart diseases, such as heart rhythm disorders and diseases of the heart muscle. Death may be the first sign of the disease in a family. Most of what is known comes from studies in North America, Europe and Australia, and there are no such data for the Brazilian population.
After a family member gives consent, the researchers will:
When a genetic cause is found, the results will be given to the responsible family member, and first-degree relatives (parents, siblings and children) will be invited to take part. Relatives who agree will give a small blood sample (about 10 mL) to test for the same genetic change. Relatives who carry the change will be referred for heart screening.
Background: Sudden cardiac death (SCD) is defined as an unexpected, non-traumatic death from cardiovascular causes occurring within 1 hour of symptom onset in an apparently healthy individual or, if unwitnessed, within 24 hours of the individual last being seen alive and asymptomatic. In individuals younger than 35 years, inherited causes predominate, including primary arrhythmia syndromes and inherited cardiomyopathies. The concept of molecular autopsy, the post-mortem genetic analysis of victims of unexplained sudden death following conventional autopsy, was introduced in 2001. Data on molecular autopsy have been reported mainly from North American, European and Australian populations, and no data are available for the admixed Brazilian population.
Study setting: This single-center prospective study involves two units of the University of São Paulo: the Death Verification Service of the City of São Paulo (SVOC-USP), where index cases are identified and samples are collected at autopsy, and the Heart Institute (InCor) of Hospital das Clínicas, University of São Paulo Medical School, where molecular and pathological analyses and cascade screening of relatives are performed.
Study workflow: At SVOC-USP, eligible cases are identified, and informed consent is obtained digitally from the legally responsible family member through the Brazilian government platform (GOV.BR). A verbal autopsy questionnaire is applied to the family, the autopsy report and death certificate are reviewed, and biological samples are collected. Whole blood (EDTA tubes) or tissue samples are sent to the Laboratory of Genetics and Molecular Cardiology (LGCM) at InCor, and the heart is sent to the InCor Pathology Laboratory.
Molecular analysis: Genomic DNA is extracted with the QIAamp DNA Blood Mini Kit and assessed for integrity (agarose gel electrophoresis), purity and concentration (NanoDrop). Whole exome sequencing is performed on the Illumina NextSeq platform, with an expected mean coverage of 100x over 95% of exonic regions. Reads are aligned to the reference genome, and variants are called with GATK HaplotypeCaller. Variants are annotated and prioritized in Franklin by Genoox, retaining variants with a minor allele frequency below 1% in gnomAD, ExAC, Bravo, Kaviar and ABraOM (a Brazilian genomic database), including intronic variants that may affect splicing. Copy number variants are also analyzed. Variants are classified according to the American College of Medical Genetics and Genomics (ACMG) criteria, and pathogenic, likely pathogenic and uncertain-significance variants are reported. Variants of uncertain significance are periodically reassessed. Secondary findings are reported only when included in the ACMG list of recommended secondary findings. Sanger sequencing is used to confirm variants with low coverage or quality and for targeted testing of relatives.
Pathological analysis: The heart is weighed after washing the cavities, and a transmural ventricular myocardial sample is stored in liquid nitrogen. After formalin fixation, the heart is examined macroscopically for myocardial fibrosis, fatty infiltration, hypertrabeculation, wall thickness disproportion, valve and septal integrity, and coronary artery origin, course and patency. Five myocardial samples and the mitral and aortic valves are sampled for histology (hematoxylin-eosin), with C4d immunohistochemistry when acute ischemic injury is suspected.
Cascade screening: When a pathogenic or likely pathogenic variant is identified in the index case, first-degree relatives are invited to participate at InCor, where they provide consent and a blood sample for targeted Sanger sequencing. Carriers are referred for clinical cardiovascular screening.
Epidemiological analysis: Data on sudden death in individuals aged 5 to 50 years are obtained from the Brazilian Ministry of Health database (DATASUS).
Data management and analysis: Data are collected and stored in REDCap, with participants identified only by a coded center and sequential number. Results are summarized using descriptive statistics.
623 studies on the registry are indexed under Tachycardia; 81 are open to participants now.
This study's planned enrollment of 200 is above the median of 149 across 208 observational studies indexed under Tachycardia.
Browse Tachycardia studies →University of Sao Paulo is the lead sponsor of 1,005 studies on the registry; 90 are open to participants now.
Of its 7 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
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individuals aged 1 to 50 years with unexplained sudden death who undergo autopsy at the Death Verification Service of the City of São Paulo (SVOC-USP), São Paulo, Brazil. First-degree relatives: parents, siblings and children of index cases in whom a pathogenic or likely pathogenic variant associated with inherited cardiac disease is identified, evaluated at the Heart Institute (InCor), Hospital das Clínicas, University of São Paulo Medical School.
Index cases
Inclusion Criteria:
Exclusion Criteria:
- Suspected death from intoxication by toxic substances
First-degree relatives
Inclusion Criteria:
Observation
Genetic: Molecular autopsy by whole exome sequencing · Genetic: Cascade genetic screening by targeted Sanger sequencing
Post-mortem genetic testing of index cases using whole exome sequencing of DNA extracted from blood or tissue collected at autopsy, with variant classification according to ACMG criteria. Performed together with a verbal autopsy questionnaire, review of the autopsy report and death certificate, and histopathological analysis of the heart.
Also known as: Index cases
Targeted Sanger sequencing of the variant identified in the index case, using a peripheral blood sample (about 10 mL) from first-degree relatives. Carriers of pathogenic or likely pathogenic variants are referred for clinical cardiovascular screening.
Also known as: First degree relatives
Diagnostic yield of molecular autopsy
Proportion of index cases in whom a pathogenic or likely pathogenic variant associated with inherited cardiac disease is identified by whole exome sequencing, classified according to ACMG criteria.
Time frame: From sample collection at autopsy to reporting of genetic results, assessed up to 3 years
Frequency of variants of uncertain significance
Proportion of index cases with at least one variant of uncertain significance in genes associated with inherited cardiac disease, according to ACMG criteria.
Time frame: From sample collection at autopsy to reporting of genetic results, assessed up to 3 years
Distribution of genetic diagnoses by disease category
Number of index cases with pathogenic or likely pathogenic variants, by gene and disease category (primary arrhythmia syndromes, cardiomyopathies, or other inherited cardiac diseases).
Time frame: From sample collection at autopsy to reporting of genetic results, assessed up to 3 years
Histopathological findings in the heart
Proportion of index cases with macroscopic or microscopic cardiac abnormalities (such as myocardial fibrosis, fatty infiltration, hypertrophy, coronary anomalies or ischemic injury) on pathological examination.
Time frame: From autopsy to completion of pathological analysis, assessed up to 3 years
Carrier rate among first-degree relatives
Proportion of tested first-degree relatives who carry the pathogenic or likely pathogenic variant identified in the index case, assessed by targeted Sanger sequencing
Time frame: From the index case genetic report to relative testing, assessed up to 3 year
Uptake of cascade genetic screening
Number of first-degree relatives tested per index case with a pathogenic or likely pathogenic variant.
Time frame: From the index case genetic report to relative testing, assessed up to 3 years
Feasibility of the molecular autopsy workflow
Proportion of eligible cases identified at the Death Verification Service for which family consent was obtained and genetic results were successfully reported.
Time frame: From case identification to reporting of genetic results, assessed up to 3 years
Plan to share: No — Individual participant data will not be shared. The dataset includes whole exome sequencing data from deceased index cases and genetic data from their living relatives, which are highly sensitive and difficult to fully de-identify. The informed consent obtained from participants and legally responsible family members does not cover data sharing with third parties, and genetic data are classified as sensitive personal data under the Brazilian General Data Protection Law (LGPD). Aggregate results will be made available through scientific publications.
No publications or documents are linked to this record.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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