Zian H Tseng, James W Salazar, Julianne Wojciak, W Patrick Devine, Brielle A Kinkead, Matthew Yee, David Eik, Jean Feng, Andrew J Connolly, Ellen Moffatt
{"title":"Heritable Burden of Community Sudden Death by Autopsy and Molecular Phenotyping for Precision Genotype Correlation.","authors":"Zian H Tseng, James W Salazar, Julianne Wojciak, W Patrick Devine, Brielle A Kinkead, Matthew Yee, David Eik, Jean Feng, Andrew J Connolly, Ellen Moffatt","doi":"10.1016/j.jacep.2024.10.027","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Sudden cardiac death (SCD) genetic studies neglect the majority occurring in older decedents with cardiovascular pathology.</p><p><strong>Objectives: </strong>This study sought to determine the burden of genetic disease in unselected adult sudden deaths by precision genotype-postmortem phenotype correlation.</p><p><strong>Methods: </strong>The authors used autopsy, histology, and toxicology to adjudicate cause and identify high-suspicion phenotypes (eg, hypertrophic cardiomyopathy) among presumed SCDs aged 18 to 90 years referred to the county medical examiner from February 2011 to January 2018. They tested 231 genes associated with sudden death and correlated genotype with postmortem phenotypes, including myocardial analysis. Family history in high-suspicion phenotype cases was obtained.</p><p><strong>Results: </strong>Of 856 autopsied presumed SCDs, families of 359 consented and 306 cases (66% cardiac cause) ultimately underwent genetic testing (mean age 62 years, 74% male). Seventy-five cases met high-suspicion phenotype criteria (8.8%), of which 36 underwent testing; 18 families met with a genetic counselor. We found 14 cases with autosomal dominant or X-linked pathogenic/likely pathogenic (P/LP) variants (apparent yield 4.6%); 6 had concordant cause (corrected yield 2%). Yields restricted to autopsy-confirmed cardiac causes (2.5%) and high-suspicion phenotypes (2.7%) were similar. Myocardial genotyping in 14 high-suspicion decedents matched negative blood genotyping, thus did not support somatic mosaicism. Myocardial RNA in a P/LP PKP2 carrier without phenotype demonstrated nonsense-mediated escape as potential mechanism for incomplete penetrance. One-half of high-suspicion cases had a family history of a related condition or sudden death.</p><p><strong>Conclusions: </strong>In this 7-year countywide study, 2% of total sudden deaths and 2.5% of confirmed SCDs had identifiable genetic cause, corrected for genotype-phenotype concordance. These results do not support routine genetic testing for community sudden deaths, particularly without autopsy.</p>","PeriodicalId":14573,"journal":{"name":"JACC. Clinical electrophysiology","volume":" ","pages":""},"PeriodicalIF":8.0000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JACC. Clinical electrophysiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jacep.2024.10.027","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Sudden cardiac death (SCD) genetic studies neglect the majority occurring in older decedents with cardiovascular pathology.
Objectives: This study sought to determine the burden of genetic disease in unselected adult sudden deaths by precision genotype-postmortem phenotype correlation.
Methods: The authors used autopsy, histology, and toxicology to adjudicate cause and identify high-suspicion phenotypes (eg, hypertrophic cardiomyopathy) among presumed SCDs aged 18 to 90 years referred to the county medical examiner from February 2011 to January 2018. They tested 231 genes associated with sudden death and correlated genotype with postmortem phenotypes, including myocardial analysis. Family history in high-suspicion phenotype cases was obtained.
Results: Of 856 autopsied presumed SCDs, families of 359 consented and 306 cases (66% cardiac cause) ultimately underwent genetic testing (mean age 62 years, 74% male). Seventy-five cases met high-suspicion phenotype criteria (8.8%), of which 36 underwent testing; 18 families met with a genetic counselor. We found 14 cases with autosomal dominant or X-linked pathogenic/likely pathogenic (P/LP) variants (apparent yield 4.6%); 6 had concordant cause (corrected yield 2%). Yields restricted to autopsy-confirmed cardiac causes (2.5%) and high-suspicion phenotypes (2.7%) were similar. Myocardial genotyping in 14 high-suspicion decedents matched negative blood genotyping, thus did not support somatic mosaicism. Myocardial RNA in a P/LP PKP2 carrier without phenotype demonstrated nonsense-mediated escape as potential mechanism for incomplete penetrance. One-half of high-suspicion cases had a family history of a related condition or sudden death.
Conclusions: In this 7-year countywide study, 2% of total sudden deaths and 2.5% of confirmed SCDs had identifiable genetic cause, corrected for genotype-phenotype concordance. These results do not support routine genetic testing for community sudden deaths, particularly without autopsy.
期刊介绍:
JACC: Clinical Electrophysiology is one of a family of specialist journals launched by the renowned Journal of the American College of Cardiology (JACC). It encompasses all aspects of the epidemiology, pathogenesis, diagnosis and treatment of cardiac arrhythmias. Submissions of original research and state-of-the-art reviews from cardiology, cardiovascular surgery, neurology, outcomes research, and related fields are encouraged. Experimental and preclinical work that directly relates to diagnostic or therapeutic interventions are also encouraged. In general, case reports will not be considered for publication.