Abstract：
BACKGROUND: Few reports describe the yield of postmortem genetic testing from medical examiners\' offices or correlate genetic test results with autopsy-confirmed phenotypes from a large cohort.
OBJECTIVE: To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States\' largest medical examiner office.
METHODS: Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated.
RESULTS: The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (P<.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in MYBPC3, TTN, PKP2, SCN5A, MYH7, and FLNC. Ten P/LPVs were novel.
CONCLUSIONS: Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members.
OBJECTIVE: To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States\' largest medical examiner office.
METHODS: Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated.
RESULTS: The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (P<.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in MYBPC3, TTN, PKP2, SCN5A, MYH7, and FLNC. Ten P/LPVs were novel.
CONCLUSIONS: Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members.
摘要：
背景：很少有报告描述来自体检医师办公室的死后基因检测结果，或将来自大型队列的尸检证实的表型与基因检测结果相关联。
目的：报告心肌病和心律失常相关基因检测的结果，以及在美国最大的医学检验员办公室调查的病例的尸检结果。
方法：回顾了2015年至2022年使用心肌病和心律失常相关基因小组测试的死后病例。使用美国医学遗传学和基因组学学院/分子病理学协会指南对变异致病性进行分类。评估了致病性/可能的致病性变异（P/LPV）与心脏病理学的相关性。
结果：该队列包括1107名不同年龄和种族的死者。在87例（7.9％）中检测到P/LPV，在心肌病和心律失常基因中有73和14种变异，分别。在437例（39.5％）中检测到不确定意义的变异。心肌病患者的诊断率（P/LPV百分比）（26.1％）明显高于无心肌病患者（P<0.0001）。婴儿的诊断率（0.7％）明显低于老年组（1至74岁，5.7%-25.9%），它们的产量之间没有统计学差异。心脏尸检结果对肥厚型心肌病的诊断率为54.0%，47.1％为心律失常性心肌病，20.0%为心肌纤维化，扩张型心肌病为19.0%，心肌炎为11.3%。大多数P/LPV在MYBPC3，TTN，PKP2,SCN5A,MYH7和FLNC。十个P/LPV是新颖的。
结论：我们的结果支持对所有年龄的心肌病患者进行死后基因检测的重要性，不足以诊断特定心肌病的心脏病变(例如，心肌纤维化)，和心肌炎.联合验尸心脏检查和遗传分析有利于准确确定死亡的根本原因并为家庭成员提供有效的临床护理。
目的：报告心肌病和心律失常相关基因检测的结果，以及在美国最大的医学检验员办公室调查的病例的尸检结果。
方法：回顾了2015年至2022年使用心肌病和心律失常相关基因小组测试的死后病例。使用美国医学遗传学和基因组学学院/分子病理学协会指南对变异致病性进行分类。评估了致病性/可能的致病性变异（P/LPV）与心脏病理学的相关性。
结果：该队列包括1107名不同年龄和种族的死者。在87例（7.9％）中检测到P/LPV，在心肌病和心律失常基因中有73和14种变异，分别。在437例（39.5％）中检测到不确定意义的变异。心肌病患者的诊断率（P/LPV百分比）（26.1％）明显高于无心肌病患者（P<0.0001）。婴儿的诊断率（0.7％）明显低于老年组（1至74岁，5.7%-25.9%），它们的产量之间没有统计学差异。心脏尸检结果对肥厚型心肌病的诊断率为54.0%，47.1％为心律失常性心肌病，20.0%为心肌纤维化，扩张型心肌病为19.0%，心肌炎为11.3%。大多数P/LPV在MYBPC3，TTN，PKP2,SCN5A,MYH7和FLNC。十个P/LPV是新颖的。
结论：我们的结果支持对所有年龄的心肌病患者进行死后基因检测的重要性，不足以诊断特定心肌病的心脏病变(例如，心肌纤维化)，和心肌炎.联合验尸心脏检查和遗传分析有利于准确确定死亡的根本原因并为家庭成员提供有效的临床护理。
