Abstract 2723: Large Genomic Deletions in Plakophilin-2 are a Rare Cause of ARVD/C and ARVD/C-like Disease.
Introduction: Plakophilin-2 (PKP2) is the major genetic determinant of ARVD/C in the Netherlands. Mutations have been found in 43 out of 82 index cases (52%), diagnosed in accordance with the 1994 Task Force criteria (TFC). A total of 15 different mutations were detected, most of them nonsense (7), frameshift (2) and splice mutations (3), suggesting haploinsufficiency (loss of function) of PKP2 as the predominant mechanism in the etiology of ARVD/C. Since many of these mutations are probably functional null alleles, it was hypothesized that large deletions within - or encompassing - the PKP2 gene can also predispose to ARVD/C.
Aim: to determine whether large deletions in PKP2 underlie apparently PKP2 negative ARVD/C cases.
Methods: a multiple ligation-dependent probe amplification kit was developed to determine copy number of all 14 exons of the PKP2 gene. In total 120 patients were included that had been referred for PKP2 testing, and that had tested negative with direct sequencing or denaturing gradient gel electrophoresis. Twenty-six patients had definite ARVD/C (TFC: ≥ 4 pts), 11 patients scored 3 pts and 83 patients scored less than 3 pts or had insufficient clinical data.
Results: a single deletion was detected encompassing the first 4 exons and promoter region of the PKP2 gene. The patient, a 35 year old male, had experienced near-syncope during exercise. Mild dilation of the right ventricle (1 pt), negative T-waves in V1-V5 (1 pt) and short VT’s with LBBB morphology during exercise testing were found (1 pt). There were frequent PVC’s. The father also carried the deletion. A third degree paternal relative died suddenly at age 28 during exercise.
Conclusion: large genomic deletions of PKP2, that go unnoticed with sequencing, can cause ARVD/C-like disease. Comprehensive testing of PKP2 should include assessment of copy number. However, the frequency of large deletions seems to be low. Since the detected deletion includes the promoter and the transcription initiation site, no protein can be derived from the affected allele. This patient demonstrates that complete loss of one PKP2 allele does not necessarily lead to more severe ARVD/C. This is in keeping with the concept of haploinsufficiency and the assumption that many PKP2 mutations cause functional null alleles.