A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy

Clin Genet. 2015 Aug;88(2):172-6. doi: 10.1111/cge.12458. Epub 2014 Sep 8.


Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non-desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal-averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24-h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC.

Keywords: Cypher/ZASP; LDB3; arrhythmogenic right ventricular cardiomyopathy; next generation sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmogenic Right Ventricular Dysplasia / diagnosis
  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Bundle-Branch Block / diagnosis
  • Bundle-Branch Block / genetics
  • Desmosomes / genetics
  • Electrocardiography
  • Family
  • Female
  • Genetic Association Studies
  • Genetic Testing
  • High-Throughput Nucleotide Sequencing
  • Humans
  • LIM Domain Proteins / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense / genetics
  • Pedigree


  • Adaptor Proteins, Signal Transducing
  • LDB3 protein, human
  • LIM Domain Proteins