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.
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。