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Abstract：
Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy with a prevalence of about 1:200. It is characterized by left ventricular hypertrophy, diastolic dysfunction and interstitial fibrosis; HCM might lead to sudden cardiac death (SCD) especially in the young. Due to low autopsy frequencies of sudden unexplained deaths (SUD) the true prevalence of SCD and especially of HCM among SUD remains unclear. Even in cases of proven SCD genetic testing is not a routine procedure precluding appropriate risk stratification and counseling of relatives.
Here we report a case of SCD in a 19-year-old investigated by combined forensic and molecular autopsy.
During autopsy of the index-patient HCM was detected. As no other possible cause of death could be uncovered by forensic autopsy the event was classified as SCD. Molecular autopsy identified two (probably) pathogenic genetic variants in FHL1 and MYBPC3. The MYBPC3 variant had an incomplete penetrance. The FHL1 variant was a de novo mutation. We detected reduced FHL1 mRNA levels and no FHL1 protein in muscle samples suggesting nonsense-mediated mRNA decay and/or degradation of the truncated protein in the SCD victim revealing a plausible disease mechanism.
The identification of the genetic cause of the SCD contributed to the rational counseling of the relatives and risk assessment within the family. Furthermore our study revealed evidences for the pathomechanism of FHL1 mutations.
Here we report a case of SCD in a 19-year-old investigated by combined forensic and molecular autopsy.
During autopsy of the index-patient HCM was detected. As no other possible cause of death could be uncovered by forensic autopsy the event was classified as SCD. Molecular autopsy identified two (probably) pathogenic genetic variants in FHL1 and MYBPC3. The MYBPC3 variant had an incomplete penetrance. The FHL1 variant was a de novo mutation. We detected reduced FHL1 mRNA levels and no FHL1 protein in muscle samples suggesting nonsense-mediated mRNA decay and/or degradation of the truncated protein in the SCD victim revealing a plausible disease mechanism.
The identification of the genetic cause of the SCD contributed to the rational counseling of the relatives and risk assessment within the family. Furthermore our study revealed evidences for the pathomechanism of FHL1 mutations.
摘要：
肥厚型心肌病（HCM）是一种遗传性心肌病，患病率约为1：200。它的特点是左心室肥厚，舒张功能障碍和间质纤维化；HCM可能导致心脏猝死（SCD），尤其是在年轻人中。由于原因不明的猝死（SUD）的尸检频率较低，因此SUD中SCD尤其是HCM的真实患病率尚不清楚。即使在经过证实的SCD情况下，基因检测也不是常规程序，排除了适当的风险分层和亲属咨询。
在这里，我们报告了一个19岁的SCD病例，通过法医和分子尸检相结合进行调查。
在索引患者的尸检期间检测到HCM。由于法医尸检无法发现其他可能的死亡原因，因此该事件被归类为SCD。分子尸检确定了FHL1和MYBPC3中的两种（可能）致病性遗传变异。MYBPC3变体具有不完全的外显率。FHL1变体是从头突变。我们在肌肉样品中检测到FHL1mRNA水平降低，并且没有FHL1蛋白，这表明SCD受害者中无义介导的mRNA衰减和/或截短蛋白的降解揭示了一种合理的疾病机制。
SCD遗传原因的鉴定有助于亲属的合理咨询和家庭内的风险评估。此外，我们的研究揭示了FHL1突变的病理机制的证据。
在这里，我们报告了一个19岁的SCD病例，通过法医和分子尸检相结合进行调查。
在索引患者的尸检期间检测到HCM。由于法医尸检无法发现其他可能的死亡原因，因此该事件被归类为SCD。分子尸检确定了FHL1和MYBPC3中的两种（可能）致病性遗传变异。MYBPC3变体具有不完全的外显率。FHL1变体是从头突变。我们在肌肉样品中检测到FHL1mRNA水平降低，并且没有FHL1蛋白，这表明SCD受害者中无义介导的mRNA衰减和/或截短蛋白的降解揭示了一种合理的疾病机制。
SCD遗传原因的鉴定有助于亲属的合理咨询和家庭内的风险评估。此外，我们的研究揭示了FHL1突变的病理机制的证据。
