73-04: Cardiac phenotype and prognosis of patients with mutations in NKX2.5 gene Free

Introduction: Mutations in NKx2.5 gene are a cause of familial forms of atrial septal defect (ASD) associated with atrioventricular conduction disturbances and unexplained sudden death (SD) but cardiac phenotype has not been described in a large population of patients with NkX2.5 mutations.

Methods: all successive patients with mutations in NKx2.5 gene diagnosed in France were included.

Results: 48 pts carried NkX2.5 gene mutations (24 men, median 24 yo, 0 to 69) (18 unrelated families, median 3 mutated subjects/family). There was an history of SD in 8 and of pace-maker implantation in 5 families. ASD (ostium secundum) was present in 36 (75%) (surgically corrected in 26 and percutaneoulsy in 3) and ventricular septal defect (VSD) in 10 (21%). Conduction disturbances were observed in 40 (90%). 22 pts developped complete or high degree permanent or paroxysmal AV block. Available ECGs showed a mean heart rate of 78 ± 19 bpm, with a PR interval of 232 ± 55 ms, a QRS duration of 88 ± 15 ms and a QTc of 461 ± 61 ms. Electrophysiological study was performed in 16 pts (AH interval 182 ± 66 ms, increased AH interval in all but two cases, HV 49 ± 23 ms, 3 patients with HV interval > 55 ms).

A pace-maker was implanted in 20 pts (42%) (with ICD in 5) and a loop recorder in one. Sustained or nonsustained ventricular tachycardia were observed in 8 pts. Mean ventricular pacing % was 79 ± 37. Eight pts were dependent of the pace-maker. Three patients deceased over the follow-up (1 SD, 1 meningitis and 1 endocarditis). 12 pts developed paroxysmal or permanent supraventricular arrhythmias (mainly atrial fibrillation). Two pts displayed dilated cardiomyopathy, 4 had left ventricular (LV) hypertrophy and 5 with features of noncompacted LV. LV ejection fraction was normal in 42 pts.

Conclusion: carriers of NkX2.5 gene mutations harbor a rich phenotype associating most of the time ASD and/or VSD together with evolutive AV block leading to pace-maker/ICD implantation in a significant part of them. Associated LV cardiomyopathy is less frequent but ventricular arrhythmias appear common and SD may happen.