Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China.
State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Int J Cardiol. 2019 Mar 15;279:122-125. doi: 10.1016/j.ijcard.2018.12.075. Epub 2018 Dec 28.
Pathogenic variants in human phospholamban coding gene (PLN) are known to cause hereditary dilated cardiomyopathy with heart failure in an autosomal dominant mode.
We performed high-depth targeted next-generation sequencing using a cardiomyopathy-panel containing 80 disease-related genes in 650 unrelated patients with non-ischemic cardiomyopathy to identify potential pathogenic PLN variants. To comprehensively evaluate the genetic cause of the proband and his pedigree, whole-exome sequencing and Sanger sequencing were performed.
A novel homozygous nonsense variant (p.Glu2Ter, c.4G>T) in PLN was identified in a 36-year-old male suffering from dilated cardiomyopathy with severe heart failure. No more cardiomyopathy-causing variant or likely pathogenic copy number variation was identified. This variant was not detected in 800 unrelated healthy controls. Furthermore, the variant is not in the Exome Aggregation Consortium or the Genome Aggregation databases. Western blots showed that this variant significantly reduced the expression of phospholamban. Furthermore, in pedigree analysis, we found that all five heterozygous PLN-p.Glu2Ter carriers (including four elder relatives) had normal heart size and cardiac function, which revealed a novel autosomal recessive inheritance mode.
Our study identified a novel pathogenic variant of PLN, and revealed a novel pathogenic inheritance mode of PLN causing dilated cardiomyopathy with heart failure.
已知人类磷酸化肌球蛋白结合蛋白 C 编码基因 (PLN) 的致病性变异以常染色体显性模式导致心力衰竭的遗传性扩张型心肌病。
我们对 650 名非缺血性心肌病的无关联患者使用包含 80 个疾病相关基因的心肌病面板进行了高通量靶向下一代测序，以鉴定潜在的致病性 PLN 变异。为了全面评估先证者及其家系的遗传原因，进行了全外显子组测序和 Sanger 测序。
在一名 36 岁患有扩张型心肌病和严重心力衰竭的男性中，发现了 PLN 中的一种新的纯合无义变异（p.Glu2Ter，c.4G>T）。未发现其他引起心肌病的变异或可能的致病性拷贝数变异。该变异未在 800 名无关健康对照中检出。此外，该变异不在 Exome Aggregation Consortium 或 Genome Aggregation 数据库中。Western blot 显示该变异显著降低了磷酸化肌球蛋白结合蛋白 C 的表达。此外，在系谱分析中，我们发现所有 5 名杂合 PLN-p.Glu2Ter 携带者（包括 4 位年长亲属）的心脏大小和心脏功能均正常，这揭示了一种新的常染色体隐性遗传模式。
我们的研究鉴定了 PLN 的一种新的致病性变异，并揭示了 PLN 导致心力衰竭的扩张型心肌病的一种新的致病性遗传模式。
