Zongzhe Li1, Peng Chen1, Jinchao Xu1, Bo Yu1, Xianqing Li1, Dao Wu Wang2, Dao Wen Wang3. 1. 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. 2. State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China. Electronic address: david37212@hotmail.com. 3. 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. Electronic address: dwwang@tjh.tjmu.edu.cn.
Abstract
BACKGROUND: Pathogenic variants in human phospholamban coding gene (PLN) are known to cause hereditary dilated cardiomyopathy with heart failure in an autosomal dominant mode. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our study identified a novel pathogenic variant of PLN, and revealed a novel pathogenic inheritance mode of PLN causing dilated cardiomyopathy with heart failure.
BACKGROUND: Pathogenic variants in human phospholamban coding gene (PLN) are known to cause hereditary dilated cardiomyopathy with heart failure in an autosomal dominant mode. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our study identified a novel pathogenic variant of PLN, and revealed a novel pathogenic inheritance mode of PLN causing dilated cardiomyopathy with heart failure.