Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families.

A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.

A case report showing unusual atrial communication with severe regurgitation of multiple valves and pulmonary aneurysm: double atrial septum with persistent interatrial space.

BACKGROUND: We discuss an unusual association: double atrial septum, pulmonary artery aneurysm, and severe regurgitation of multiple valves. CASE SUMMARY: A 70-year-old man was admitted into the hospital because of progressive dyspnoea. Physical examination showed a blood pressure of 132/70 mmHg, a systolic murmur on the right upper sternal border, another systolic murmur at the apex, and a diastolic murmur at the lower left sternal border. Electrocardiogram revealed atrial fibrillation and complete left bundle branch block. Transthoracic echocardiography showed mitral prolapse, severe mitral, aortic, and pulmonary regurgitation, a 60 mm diameter pulmonary artery aneurysm, mild to moderate tricuspid regurgitation, and moderate pulmonary hypertension. Transoesophageal echocardiography also showed an unusual atrial communication consisting of a double atrial septum with a mid-line chamber between both atria. A cardiac magnetic resonance scan was performed and confirmed echocardiography findings and QP:QS ratio = 1.3. DISCUSSION: In our knowledge, this is the first case report with this association. We present the main clinical features of the double atrial septum with persistent interatrial space, its echocardiography anatomy, differential diagnosis, and embryology.