Multicenter Experience for Early and Mid-Term Outcome of MyVal Transcatheter Pulmonary Valve Implantation.

Transcatheter pulmonary valve implantation (TPVI) is a surgical alternative for correcting dysfunctional right ventricular outflow tract in previously operated patients. MyVal transcatheter heart valve (THV) (Meril Life Sciences, India), a new transcatheter valve designed for aortic position has recently been reported to be implanted in pulmonary position. Myval transcatheter valve were implanted in patients with stenosed dysfunctional conduits, severe regurgitation from transannular patch or dysfunctional surgical pulmonary valves (Bioprosthesis). Procedural details and post-TPVI follow-up were analysed. Myval TPVI was used in Fifty three patients with median age of 15 years (IQR 12-19.5 years). Almost sixty percent of the patients were male, with a median weight of 50 kg (31-63 kg). Prestenting was used in more than 80 percent of patients (n = 45 patients), while 6 patients had a prior surgical valve implantation. After Myval TPVI implantation, the peak instantaneous gradient across the RVOT decreased from a median of 23.5 mmHg (IQR 10-53 mmHg) pre-procedure to 10 mmHg (IQR 5-16 mmHg) post-procedure. The median fluoroscopy time for the procedure was 35 min (IQR 23.5-44 min). The large sizes-mainly the 29-mm and 32 mm Myval (Navigator, Meril Life Sciences Pvt Ltd, India), were the most used size in 40% (n = 22) of the cases each. The median contrast volume used during the procedure was 247 mL (IQR 120-300 mL). Patients were followed for a median period of 360 days (IQR 164-525 days). At the last clinic follow-up, there was no tricuspid valve regurgitation. Moderate neo-pulmonary valve regurgitation was reported in three cases. Early experience of TPVI with MyVal is encouraging with procedural success in all patients and acceptable mid-term outcomes.

Short- and medium-term outcomes for patent ductus arteriosus stenting in neonates ≤2.5 kg with duct-dependent pulmonary circulation.

BACKGROUND: Morbidity with surgical systemic-to-pulmonary artery shunting (SPS) in infants ≤2.5 kg has remained high. Patent ductus arteriosus (PDA) stenting may be a valid alternative. The objective of this study is to evaluate outcomes following PDA stenting in patients ≤2.5 kg from four large tertiary centers. METHODS: Retrospective review of all neonates ≤2.5 kg with duct-dependent pulmonary circulation who underwent PDA stenting. Procedural details, pulmonary arterial growth, reinterventions, surgery type, and outcomes were assessed. RESULTS: PDA stents were implanted in 37 of 38 patients attempted (18 female) at a median procedural weight of 2.2 kg (interquartile range [IQR], 2-2.4 kg). Seven patients (18%) had a genetic abnormality and 16 (42%) had associated comorbidities. The median intensive care unit stay was 4 days (IQR, 2-6.75 days), and the median hospital stay was 20 days (IQR, 16-57.25). One patient required a rescue shunt procedure, with three others requiring early SPS (<30 days postprocedure). Twenty patients (54%) required reintervention with either balloon angioplasty, restenting, or both. At 6-month follow-up, right pulmonary artery growth (median z-score -1.16 to 0.01, p = 0.05) was greater than the left pulmonary artery (median z-score -0.9 to -0.64, p = 0.35). Serious adverse effects (SAEs) were seen in 18% (N = 7) of our cohort. One patient developed an SAE during planned reintervention There were no intraprocedural deaths, with one early procedure-related mortality, and three interstage mortalities not directly related to PDA stenting. CONCLUSIONS: PDA stenting in infants ≤2.5 kg is feasible and effective, promoting pulmonary artery growth. Reintervention rates are relatively high, though many are planned to allow for optimal growth before a definitive operation.

Transcatheter mitral valve-in-valve implantation in a pediatric patient.

An 11-year-old girl, with 25 mm mosaic tissue valve presented with clinical and echocardiographic appearance of stenotic mitral valve prosthesis. Her condition was treated via a transcatheter valve-in-valve implantation using a 23 mm Edwards Sapien 3, with satisfactory outcome.

Transcatheter Tricuspid Valve-in-Valve Implantation for the Treatment of Dysfunctional Surgical Bioprosthetic Valves: An International, Multicenter Registry Study.

BACKGROUND: Off-label use of transcatheter aortic and pulmonary valve prostheses for tricuspid valve-in-valve implantation (TVIV) within dysfunctional surgical tricuspid valve (TV) bioprostheses has been described in small reports. METHODS AND RESULTS: An international, multicenter registry was developed to collect data on TVIV cases. Patient-related factors, procedural details and outcomes, and follow-up data were analyzed. Valve-in-ring or heterotopic TV implantation procedures were not included. Data were collected on 156 patients with bioprosthetic TV dysfunction who underwent catheterization with planned TVIV. The median age was 40 years, and 71% of patients were in New York Heart Association class III or IV. Among 152 patients in whom TVIV was attempted with a Melody (n=94) or Sapien (n=58) valve, implantation was successful in 150, with few serious complications. After TVIV, both the TV inflow gradient and tricuspid regurgitation grade improved significantly. During follow-up (median, 13.3 months), 22 patients died, 5 within 30 days; all 22 patients were in New York Heart Association class III or IV, and 9 were hospitalized before TVIV. There were 10 TV reinterventions, and 3 other patients had significant recurrent TV dysfunction. At follow-up, 77% of patients were in New York Heart Association class I or II (P<0.001 versus before TVIV). Outcomes did not differ according to surgical valve size or TVIV valve type. CONCLUSIONS: TVIV with commercially available transcatheter prostheses is technically and clinically successful in patients of various ages across a wide range of valve size. Although preimplantation clinical status was associated with outcome, many patients in New York Heart Association class III or IV at baseline improved. TVIV should be considered a viable option for treatment of failing TV bioprostheses.

A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function.

Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects, such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects and may be attributed to incorrect establishment of body laterality. Here, we identify new patients with dextrocardia who have mutations in CFAP53, a coiled-coil domain containing protein. To elucidate the mechanism by which CFAP53 regulates embryonic asymmetry, we used genome editing to generate cfap53 zebrafish mutants. Zebrafish cfap53 mutants have specific defects in organ laterality and randomization of asymmetric gene expression. We show that cfap53 is required for cilia rotation specifically in Kupffer's vesicle, the zebrafish laterality organ, providing a mechanism by which patients with CFAP53 mutations develop dextrocardia and heterotaxy, and confirming previous evidence that left-right asymmetry in humans is regulated through cilia-driven fluid flow in a laterality organ.

Acquired aortic atresia: Catheter therapy using covered stents.

INTRODUCTION: To maintain aortic continuity, aortic arch interruption is usually treated surgically. We present our experience of aortic arch reconstruction using percutaneous implantation of covered stents and mid-term follow-up. OBJECTIVE: To describe the feasibility, safety, and effectiveness using percutaneous placement of covered stents for functional aortic atresia and mid-term follow-up. METHODS: Nine patients (7 males), mean age of 30.8 ±16.2 years (range 13-58 years) and mean body weight of 65.7± 14.9 kg (range 52-95 kg), were investigated for systemic hypertension and found to have functional aortic interruption. All were treated with percutaneous perforation, combined with balloon dilation and implantation of covered stents. After stent implantation, control angiograms were performed. RESULTS: All the patients had functional aortic interruption and continuity was established by perforating the atretic segment with trans-septal Brockenbrough needle or the stiff end of a guide wire. A covered Cheatham-Platinum CP stent was used to establish the luminal continuity of the aortic arch. Angiograms after stent deployment showed good forward flow through the stent and hemodynamic assessment revealed minimal gradients across the stent. The mean invasive descending aortic systolic blood pressure before stenting was 86.6 ± 14.3 mm Hg, which increased to 116.5 ± 16.3 mm Hg, after stenting (P = 0.004). The mean invasive descending aortic diastolic blood pressure before stenting was 63.6 ± 8.1 mm Hg, which increased to 79.7 ± 13.3 mm Hg after stenting (P = 0.002). CONCLUSION: Percutaneous treatment of functional aortic atresia with covered stents is feasible, safe, and effective alternative to surgery with excellent short- and mid-term results.

Images of Percutaneous Closure of Ruptured Sinus of Valsalva.

The images of transcatheter closure of ruptured sinus of valsalva are presented.

Recombinant Tissue Plasminogen Activator in the Treatment of Neonates with Intracardiac and Great Vessels Thrombosis.

Life-threatening intracardiac and great vessels thrombi are rare in neonates. Recombinant tissue plasminogen activator (rTPA) is used in adults to stimulate fibrinolysis and facilitate thrombus resolution. Its use in neonates, along with heparin, remains controversial because of potential risk of serious bleeding. We aim to present our experience with the use of thrombolytic agents in seven neonates and young infants. In a retrospective study, over a period of 6 years, the medical records of neonates and young infants, who were diagnosed with intracardiac and great vessels thrombi, were reviewed. The following factors were collected: demographic data, primary diagnosis, thrombus site, risk factors, method of diagnosis, thrombolytic and/or anticoagulation agent, route, dose and duration of treatment, complications, and outcome. Six neonates and one 45-day-old infant were analyzed. Age ranged from 5 to 45 days (median age 12 days), and median weight was 2.9 kg (range 0.9-3.8 kg). The thrombi were diagnosed by echocardiography in five and by angiography in two cases. All patients had life-threatening thrombi; four were treated with rTPA (0.5 mg kg(-1) h(-1)) and heparin infusions with complete dissolution of the thrombi, within a median time of 60 h (6-72 h), and without complications. The remaining three patients (two who were premature, at 28 and 34 weeks of gestation, and the third who had a deranged coagulation profile) were treated with unfractionated heparin due to fear of bleeding. The thrombi dissolved in the premature babies (within 2 weeks and 3 months, respectively) but embolized and resulted in the death of the third infant after 2 weeks of treatment. The current case series confirmed the effectiveness and safety of intravenous rTPA infusion, at the dosages used, in neonates and young infants with life-threatening thrombi.

Recanalization of arterial duct is feasible, effective and its potential risks are treatable.

BACKGROUND: Recanalization of arterial duct (AD) is rarely needed. OBJECTIVE: The aim of this study is to report our experience regarding the feasibility and effectiveness of arterial duct recanalization in three infants and review the relevant literature. METHODS AND RESULTS: We report on three patients with decreased pulmonary blood flow after initial palliation. The first patient had pulmonary atresia (PA) and an intact ventricular septum. He needed recanalization of the AD after pulmonary valve perforation and dilatation. The second patient had PA and ventricular septal defect (VSD). His AD originated from the left subclavian artery. He required AD recanalization after palliation with a central shunt and clipping of the duct. During intervention he developed a thrombus in the stent, which was treated successfully using thrombolytic treatment. The third patient had PA and VSD. The arterial duct originated from the left subclavian artery and was recanalized after spontaneous closure despite prostaglandin infusion. During the procedure the patient had severe desaturation and bradycardia requiring resuscitation fortwo minutes. All infants had successful arterial duct recanalization and stenting. Additionally, they were clinically stable during follow-up. CONCLUSION: Arterial duct recanalization and stenting is a feasible and effective procedure in selected cases, and its risks are treatable. Long-term studies are required.

Percutaneous removal of right atrial thrombus by suction technique.

We present a case of percutaneous removal of a large right atrial thrombus formed after insertion of a ventriculoatrial shunt for hydrocephalus.

Post Melody valve implant in a conduit with regurgitant native outflow tract successful closure by Amplatzer muscular device.

We describe the technique of closure of native right ventricular outflow tract by Amplatzer muscular ventricular septal defect device because of severe regurgitation in a patient who had tetralogy of Fallot repair with conduit at 3 years of age followed by percutaneous Melody valve implant 6 years later.

Combined semilunar valve stenoses in neonates: management approaches and literature review.

Combination of right and left ventricular outflow tracts obstruction is extremely rare. Neonates with combined aortic stenosis (AS) and pulmonary stenosis (PS) present in critical condition and required urgent treatment. The management approach is not well defined. We report five female neonates with combined AS and PS presented to our institute in the last 5 years, age (1-18 days), weight (2.2-3.4 kg). Two had associated muscular ventricular septal defects. The mean Doppler gradient across the aortic valve (AV) was 73 mmHg (53-105 mmHg) and across the pulmonary valve was 62 mmHg (44-76 mmHg). Three had balloon dilatation and one surgical repair. The fifth patient was managed conservatively, but had sudden cardiac death at age of 3 months. One patient arrived in shock and sepsis, underwent emergency balloon dilation of the AV in the ICU. Despite decreasing the gradient, she died next day after the procedure. The surviving children were well at median follow-up age of 3.4 years. This is an extremely rare combination which needs early intervention. The management approach is not well defined. Interventional catheterization is possibly the better option.

Williams-Beuren syndrome: computed tomography imaging review.

Williams-Beuren syndrome (WBS) affects young infants and children. The underlying etiopathogenesis of this rare disease is due to the mutation of the elastin gene that is responsible for the elasticity of the arterial wall. As a result of inadequate elastin production, the major systemic arteries become abnormally rigid and can be manifested by an impediment to the blood flow. The most common cardiovascular abnormalities encountered in WBS are supravalvular aortic stenosis, pulmonary arterial stenosis, and mitral valve prolapse. Less frequently observed cardiovascular abnormalities include coarctation of the aorta, ventricular septal defect, patent ductus, subaortic stenosis, and hypertrophic cardiomyopathy. Coronary artery stenosis and severe impediment to the bi-ventricular outflow as a result of supravalvular aortic and pulmonary artery stenosis predispose patients to sudden death. Patients with progressed arterial stenosis and severe stenosis are likely to require intervention to prevent serious complications. Rarely, imaging findings may precede clinical presentation, which allows the radiologist to participate in the patient care. However, to be more prudent, the radiologist must be accustomed to the imaging characteristics of WBS as well as the patient's clinical information, which could raise the suspicion of WBS. We performed a retrospective analysis of all the available images from patients diagnosed with WBS in last 4 years at our institution, and present key imaging findings along with a review of the literature to summarize the clinically relevant features as demonstrated by multidetector computed tomography in WBS. Cross-sectional imaging plays a vital role in the diagnosis of WBS cases with equivocal clinical features. MDCT evaluation of complex cardiovascular abnormalities of WBS including coronary artery disease is feasible with modern MDCT scanners and in the future, this approach could provide accurate information for planning, navigation, and noninvasive assessment of the secondary arterial changes in WBS and thus reducing the dependence upon invasive contrast catherization techniques.

Cardiac care in trisomy 18: A path to improved outcomes (case report).

Background: Trisomy 18 (also known as Edwards syndrome) is a chromosomal disorder characterized by severe developmental anomalies and cognitive deficits. Cardiac complications are a leading cause of mortality in these patients, and the role of cardiac interventions remains controversial. Case Presentation: We report a case of a full-term baby girl with trisomy 18, born via elective cesarean section. The neonate presented with pulmonary atresia and a series of other cardiac abnormalities, necessitating immediate intervention. Despite the initial challenges, including a brief episode of desaturation post-intervention, the patient responded positively to a balloon pulmonary valvuloplasty and emergency patent ductus arteriosus stent insertion, illustrating the potential benefits of cardiac interventions in patients with trisomy 18. Discussion: This case highlights the successful application of cardiac interventions in a patient with trisomy 18, challenging the notion of universally denying such treatments to this population. Our findings suggest that selective interventions can improve quality of life and stabilize the condition, supporting the need for further research to establish clear guidelines for treatment in this demographic. Conclusion: This case adds to the growing evidence supporting the feasibility and potential benefits of cardiac interventions in patients with trisomy 18, advocating for a more individualized approach to treatment.

Peripheral Pulmonary Artery Stenosis Is Not a Contraindication to a Single-ventricle Pathway.

BACKGROUND: The presence of peripheral pulmonary artery stenosis (PPAS) involving lobar and/or segmental pulmonary artery (PA) branches might preclude proceeding to a single-ventricle pathway. We adopted a strict strategy for PA rehabilitation and surgical reconstruction in patients who are unable to progress to a single-ventricle pathway. METHODS: We conducted a retrospective review of 22 patients with single-ventricle physiology who underwent surgical reconstruction for PPAS from April 2008 to March 2020. Our surgical approach was single stage in 15 patients (68.2%) and 2 stage in 7 patients (31.8%) depending on the presence or absence of PA hypoplasia distal to the PPAS. RESULTS: The PPAS was type 3 (lobar) in 19 patients (86.4%) and type 4 (segmental) in 3 patients (13.6%). The mean number of PA angioplasties performed was 8 ± 5.6 per patient. There was no mortality in this series with a median of 52 months (range, 8-143) of follow-up. Twenty patients (90.9%) were able to progress in the single-ventricle pathway with 12 patients (54.5%) undergoing a Fontan operation and 8 patients (36.4%) achieving bidirectional Glenn shunt and awaiting a Fontan operation. Two patients (9.1%) were not suitable to progress to the single-ventricle pathway because of elevated PA pressure. All patients who achieved cavopulmonary connection were alive and asymptomatic with no signs of elevation of PA pressure. No patient required further reinterventions for the PA. CONCLUSIONS: PPAS is not a contraindication for single-ventricle palliation. With careful planning and aggressive early surgical reconstruction, most of these patients can successfully progress to cavopulmonary connections.

Late Outcomes After Pulmonary Arterial Reconstruction in Patients With Arterial Tortuosity Syndrome.

BACKGROUND: Surgical pulmonary artery reconstruction in patients with arterial tortuosity syndrome has excellent outcomes. In this study, we report our late outcomes after more than a decade of experience with such complex interventions. METHODS: We conducted a retrospective review of 33 arterial tortuosity syndrome patients who underwent pulmonary artery reconstruction. The mean preoperative right ventricular to left ventricular pressure ratio was 1.19 ± 0.2. Our surgical approach included either a single-stage complete repair through a median sternotomy (17 patients) or a two-stage repair through sternotomy/left thoracotomy (16 patients), depending on the degree of distal involvement in the left pulmonary artery. RESULTS: Median age was 36 months. All patients had distal segmental peripheral pulmonary artery stenosis. Thirty patients (90.1%) were symptomatic before surgery. There was one hospital death due to viral pneumonia 78 days after the surgery (in-hospital mortality 3%). The mean right ventricular to left ventricular pressure ratio decreased to 0.31 ± 0.07 early postoperatively (P < 0.001), representing a 74% reduction compared with preoperative values. Follow-up was 100% complete for all hospital survivors (32 of 33) with a mean follow-up of 70.42 ± 43.32 months (range, 2 to 143). There was no late mortality or need for reintervention (surgical or catheter based) after hospital discharge. In late postoperative catheterization, the mean right ventricular to left ventricular pressure ratio was 0.27 ± 0.05 (P = .003 compared with early postoperative value). All patients were asymptomatic on their most recent follow-up. CONCLUSIONS: A strategy of complete surgical reconstruction of all stenotic pulmonary artery segments in patients with arterial tortuosity syndrome is recommended for sustainable successful outcomes more than a decade later.

Late outcomes of surgical reconstruction of peripheral pulmonary arteries.

OBJECTIVE: The ideal management of peripheral pulmonary artery stenosis is still controversial. We adopted a primary surgical approach to this complex lesion with excellent early outcomes. In this study, we analyzed our late outcomes. METHODS: We performed a retrospective review of 91 patients with biventricular anatomy who underwent peripheral pulmonary artery reconstruction from March 2008 to July 2020. Our surgical approach included either a single-stage complete repair through median sternotomy or a 2-stage repair through sternotomy/left thoracotomy, depending on the degree of distal involvement of the left pulmonary artery branches. RESULTS: Median age was 26 months. Syndromic etiology was established in 54 patients (59.3%) versus nonsyndromic etiology in 37 patients (40.7%). Single-stage repair was achieved in 68 patients (74.7%). There were 2 (2.2%) in-hospital mortalities. The mean right ventricular to aortic systolic pressure ratio decreased from 1.07 ± 0.20 preoperatively to 0.32 ± 0.07 immediately postoperatively (P < .001), representing a 70.1% reduction. At 1-year postoperative catheterization, the mean right ventricular to aortic systolic pressure ratio was 0.28 ± 0.05 (P < .001 compared with immediately postoperative value). With a median follow-up of 68 months (IQR, 39-117.5 months), there was no late mortality after discharge. All patients were active and asymptomatic on the most recent follow-up. There were no early or late reinterventions on pulmonary arteries. CONCLUSIONS: Late outcomes of surgical reconstruction of peripheral pulmonary arteries are excellent and durable in various pathologies (syndromic and nonsyndromic) with a significant reduction in right ventricular to aortic systolic pressure ratio, low mortality, and no reintervention.

Transcatheter Mitral Valve-in-Valve Implantation in Pediatric Patients.

BACKGROUND: Transcatheter implantation of the Edwards Sapien 3 valve (Edwards Lifesciences, Irvine CA) within the bioprosthetic mitral valve (MV) is an established method of treatment in adults. However, it has not been well studied in the pediatric age group. METHODS: Transcatheter mitral valve-in-valve implantation was attempted in 4 symptomatic pediatric patients with a dysfunctional MV bioprosthesis implanted at an earlier stage due to severe MV stenosis or regurgitation. We reviewed our experience with MV implantation in this cohort. RESULTS: The mean age and weight of the patients at the time of the procedure were 11.4 years (range: 10-14 years) and 36 kg (range: 31-44 kg), respectively. The transmitral mean gradient dropped from a mean of 19.75 mm Hg (range: 15-22 mm Hg) to a mean of 1 mm Hg (range: 0-3 mm Hg) after the procedure. The mean fluoroscopy time was 55.25 minutes (range: 40-72 minutes), and the mean hospital length of stay was 4 days (range: 3-7 days). The patients' functional class improved from New York Heart Association class IV to class I during the follow-up period. CONCLUSIONS: Transcatheter mitral valve-in-valve implantation can be performed safely for dysfunctional bioprosthetic MVs in the pediatric age group with favorable early and midterm outcomes. This procedure offers a viable alternative in patients who have high surgical risk or are deemed unfit for conventional surgery. However, we still recommend a long-term study of this approach in a large cohort, multicentre study.

INTRODUCTION: L'implantation de la prothèse valvulaire Edwards Sapien 3 (Edwards Lifesciences, Irvine, CA) par cathéter dans la bioprothèse valvulaire mitrale (VM) est une méthode de traitement établie chez les adultes. Toutefois, cette méthode n'a pas fait l'objet d'études approfondies auprès d'enfants. MÉTHODES: Une tentative d'implantation valvulaire mitrale de type valve-in-valve par cathéter a été réalisée chez quatre enfants symptomatiques qui avaient une bioprothèse VM dysfonctionnelle implantée antérieurement en raison d'une sténose VM ou d'une régurgitation grave. Nous avons passé en revue notre expérience d'implantation VM auprès de cette cohorte. RÉSULTATS: L'âge et le poids moyens des patients au moment de l'intervention étaient respectivement de 11,4 ans (étendue : 10-14 ans) et de 36 kg (étendue : 31-44 kg). La moyenne du gradient moyen transmitral a baissé. Elle est passée de 19,75 mmHg (étendue : 15-22 mmHg) à 1 mmHg (étendue : 0-3 mmHg) après l'intervention. La durée moyenne de la fluoroscopie était de 55,25 minutes (étendue : 40-72 minutes), et la durée moyenne du séjour à l'hôpital était de quatre jours (fourchette : 3-7 jours). La classification fonctionnelle des patients selon la New York Heart Association a montré une baisse. Les patients sont passés de la classe IV à la classe I durant la période de suivi. CONCLUSIONS: L'implantation valvulaire mitrale de type valve-in-valve par cathéter peut être pratiquée de façon sûre chez les enfants porteurs d'une bioprothèse VM dysfonctionnelle dont les issues à court ou à moyen terme sont favorables. Cette intervention est une alternative viable pour ces patients dont le risque lié à l'intervention chirurgicale est élevé ou considérés inaptes à subir une intervention chirurgicale traditionnelle. Toutefois, nous recommandons encore une étude à long terme sur cette approche, voire une vaste étude multicentrique de cohorte.

MDCT evaluation of intramyocardial-sinusoids-coronary artery communications in a neonate with pulmonary atresia and intact ventricular septum.

A patient of tetrology of Fallot with complete atresia of the pulmonary outflow tract with ventriculocoronary connections is presented. MDCT imaging revealed left coronary sinus, with a large fistula draining into the free wall of hypoplastic right ventricular cavity with tortuous channel arising from right ventricular outflow, and communicating with proximal limb of the fistula forming a complete loop suggesting a right ventricle-to - left coronary sinus sinusoid.

An intronic mutation leading to incomplete skipping of exon-2 in KCNQ1 rescues hearing in Jervell and Lange-Nielsen syndrome.

Romano-Ward syndrome (RWs) and Jervell and Lange-Nielsen Syndrome (JLNs) are two inherited arrhythmia disorders caused by monoallelic or bi-allelic mutations, respectively, in the KCNQ1 or KCNE1 genes. Both disorders could cause Long QT syndrome either without deafness (RWs), or with deafness (JLNs). We have performed clinical, molecular and functional investigation in two consanguineous Arabian families with history of sudden death of several children. Importantly, none of the affected individuals had (or have) any hearing impairment. Homozygosity mapping followed by molecular analysis identified a novel splice acceptor site mutation (homozygously) in intron-1 of the KCNQ1 gene (c.387 -5T>A), in these two apparently unlinked families. RNA analysis revealed that this splice site mutation causes incomplete transcriptional aberration of the KCNQ1 gene, leaving 10% of the normal allele transcript intact, which restores the hearing function. Our molecular and functional data provide the first evidence that small amount (as low as 10%) of normal KCNQ1 current can effectively maintain the hearing function but fails to maintain cardiac repolarization characteristics within normal limits. Additionally, we have revealed four extra low frequency aberrant isoforms emphasizing the importance of intronic and other non-coding sequences in maintaining cellular homeostasis as pathologic changes in a single nucleotide can affect splicing events at distant sites. The novel KCNQ1 mutation found in this study is very likely a founder mutation in the southern province of Saudi Arabia emphasizing its screening in the LQT population in this region.