Clinical Features and Genetic Basis of Progressive Cardiac Conduction Defect: Japanese PCCD Registry

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Progressive cardiac conduction disturbance (PCCD) is a hereditary cardiac bundle branch disorder that often processes to complete heart block. We evaluated the clinical features and genetic basis in 61 individuals from 44 unrelated families affected by PCCD. Individuals with structural heart abnormalities at the time of diagnosis were excluded. Despite the assumption that PCCD predominates in elderly population, the age of onset showed a wide-range distribution (6–95 years). Conduction disturbance was progressively aggravated in 29 individuals (48%) and the cardiac dysfunction was manifested in 17 individuals (28%). Pacemaker or ICD was implanted in 43 individuals (70%). However, 3 patients who received pacemaker or ICD and 3 individuals who declined the device therapy died suddenly. Genetic screening revealed mutations in cardiac ion channel genes: SCN5A (n=6), KCNH2 (n=1), and GJA5 (n=1) encoding a gap junction isoform connexin 40 predominantly expressed in the conduction system. Two probands were heterozygous mutation carries. Moreover, the screening identified mutations in LMNA (n=8), the most prevalent causative genes of dilated cardiomyopathy that encodes an inner nuclear membrane protein lamin A/C. Although mutations remain unknown in most cases (n=38, 62%), mutation carries of SCN5A (57%) and LMNA (55%) progressively manifested heart failure. In conclusion, clinical features and genetic basis underlying PCCD are heterogenous.