Phenotypic Spectrum of HCN4 Mutations
A Clinical Case
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The hyperpolarization-activated cyclic nucleotide-gated (HCN) cation (Na+/K+) currents (If/Ih) are generated by 4 members of the channel family (HCN1–4).1 These currents contribute to the pacemaker function2 in heart and brain.3 The HCN4 current is known to play a crucial role in the automaticity of the sinus node through the generation of a slow diastolic depolarization during the phase 4 of the cardiac action potential.4 Thus, it is a crucial channel for appropriate pacemaker activity and conduction system function because it facilitates rapid repolarization. Interestingly, HCN4 has been shown to be expressed in essentially the entire heart tissue.5 Mutations in HCN4 have been associated mainly with sick sinus syndrome phenotype6; however, in recent years, a broad spectrum of phenotypes has been reported, including sinus bradycardia,7 inappropriate sinus tachycardia,8 early-onset atrial fibrillation,9,10 atrio-ventricular block,11,12 idiopathic ventricular tachycardia,13 left ventricular noncompaction (LVNC),14–17 dilation of the aorta, and mood and anxiety disorders.19 In the present study, we report a case with sick sinus syndrome, LVNC, mood and anxiety disorders, and ventricular fibrillation (VF) hosting 2 novel HCN4-pore mutations.
The index patient was a 36-year-old man, who presented initially with mood and anxiety disorders characterized by important depressive episodes. Previous clinical records revealed a slightly impaired left ventricular function, paroxysmal atrial fibrillation, frequent premature ventricular complexes, and nonsustained tachycardia originating from the right ventricle. Therapy with β-blocker was initiated but discontinued shortly because of profound sinus bradycardia, which did not resume after washout. A cardiac magnetic resonance imaging excluded a right ventricular cardiomyopathy. The left ventricle showed an uncommon hypertrabeculation; however, the criteria for an LVNC were not fulfilled at that time.
Eight years later, the patient was hospitalized because of heart failure and …