Saleh Alghamdi

De novo mutation in the KCNQ1 gene causal to Jervell and Lange‐Nielsen syndrome

Jervell and Lange‐Nielsen syndrome (JLNS) is an autosomal recessive disorder, clinically characterized by severe cardiac arrhythmias [due to prolonged QTc interval in electrocardiogram (ECG)] and bilateral sensory neural deafness. Molecular defects causal to JLNS are either homozygous or compound heterozygous mutations, predominantly in the KCNQ1 gene and occasionally in the KCNE1 gene. As the molecular defect is bi‐allelic, JLNS patients inherit one pathogenic mutation causal to the disorder from each parent. In this report, we show for the first time that such a disorder could also occur due to a spontaneous de novo mutation in the affected individual, not inherited from the parent, which makes this case unique unlike the previously reported JLNS cases.

Genotype-phenotype analysis of Jervell and Lange-Nielsen syndrome in six families from Saudi Arabia.

We sought to explore the genotype–phenotype of Jervell and Lange‐Nielsen syndrome (JLNS) patients in Saudi Arabia. We have also assessed the plausible effect of consanguinity into the pathology of JLNS. Six families with at least one JLNS‐affected member attended our clinic between 2011 and 2013. Retrospective and prospective clinical data were collected and genetic investigation was performed. Pathogenic mutations in the KCNQ1 gene were detected in all JLNS patients. The homozygous mutations detected were Leu273Phe, Asp202Asn, Ile567Thr, and c.1486_1487delCT and compound heterozygous mutations were c.820_ 830del and c.1251+1G>T. All living JLNS patients except one had a QTc of >500 ms and a history of recurrent syncope. β‐Blockers abolished the cardiac‐related events in all patients except two siblings with homozygous Ile567Thr mutation. Four of the six mutations were originally reported in autosomal dominant long QT syndrome (LQTS) patients. Eighty percent of the heterozygote mutation carriers showed prolongation of QTc, but majority of these reported no symptoms attributable to arrhythmias. Mutations detected in this study will be advantageous in tribe and region‐specific cascade screening of LQTS in Saudi Arabia.

Not all pathogenic mutations are pathogenic: KCNH2 mutations in two sisters with tetralogy of Fallot.

Conotruncal heart defects (OMIM #217095) include tetralogy of Fallot (TOF), double outlet right ventricle, persistent truncus arteriosus, and transposition of the great vessels, which comprise 25%–30% of non-syndromic congenital heart defects [1]. Sustained ventricular tachycardia (VT) and sudden cardiac death are a frequent late complication after repair of TOF [2]. 15%–20% of patients with TOF have a deletion in chromosome 22q11.2 [3]. Mutations in the cardiac transcription factor encoding genes and genes involved in cardiogenesis, e.g. NKX2.5, GATA4, TBX1, TBX5, TBX20, JAG1, and NOTCH1, are found in a further ~5% of the TOF patients [4]. In the majority of TOF patients, a causal genetic defect remains obscure. Here, we report two sisters, one bornwith TOF (II:1, 13 yrs) and the other with truncus arteriosus (II:2, 11 yrs) (Fig. 1). Their parents are first degree cousins. Both sisters had several corrective surgeries for their defects. After surgery, the second sister (II:2) developed complete AV block, which necessitated a single chamber ventricular pacemaker (VVI) implantation at 4 yrs. Considering the familial occurrence of the conotruncal defect, we attempted to identify a genetic etiology. Array CGH (Agilent oligoNT arr cgh 180 K, resolution: 200 Kb) revealed no pathological deletions or duplications and we proceeded to exome sequencing. No pathogenic mutations were found in any of the genes known to be involved in cardiogenesis. Intriguingly, two pathogenic mutations, p.[(Val172Met);(Arg293Cys)] in the KCNH2 gene (Fig. 1) were found in both sisters. Thesemutations were maternally inherited (I:2). Both mutations are well recognized as class-1 pathogenic mutations in long QT syndrome (LQTS), type 2 [5], however, it is unlikely that these mutations are causal for the conotruncal malformation in two sisters (II:1, II:2). Both the mother (I:2) and the youngest sister (II:4) also carried the same mutations without any conotruncal defect. Patients with conotruncal malformation are often susceptible to life threatening cardiac arrhythmias and sudden death [2]. This propensity for arrhythmia was reported to be aggravated in the presence of a pathogenic mutation or polymorphism in cardiac ion channel genes [6]. Large ICa-L window current depicted in the cardiomyocytes of the TOF children is considered responsible for Early After Depolarization (EAD) and arrhythmia [7]. Pathogenic mutations in KCNH2 also reduce the IKr current in cardiomyocytes [8]. So, when a patient has both TOF and KCNH2mutations, a combination of two opposing currents (↑ICa-L, ↓IKr) is active in the cardiomyocytes and the expected result is an augmentation of the cardiac action potential, hence a remarkable increase in QTc and arrhythmia [7,8] is envisaged. Of the two sisters (II:1, II:2) with conotruncal malformations and KCNH2 mutations, one (II:1) had a QTc of ±450 ms (Fig. 1). QTc in the second sister (II:2) could not bemeasured. Neither reported any arrhythmia related symptoms or syncope despite the presence of the two KCNH2 mutations in the highly pathogenic, pore forming region [5]. Exome sequencing is widely applied for the identification of the molecular defects in diseases which have or are presumed to have a genetic basis. Findings from our study show us that the interpretation of pathogenic mutations is not always univocal. Researchers, clinicians and geneticists ought to remain open to the possibility of reconsidering the interpretation of amutation previously associated with a given phenotype, when the mutation is found in association with an unrelated, possibly unexpected clinical phenotype. As the mutations identified in two siblings are proven LQTS causal mutations, we analyzed whether the mutations have any additional impact on arrhythmia propensity on children with conotruncal defects. We have not observed any particular positive penetrance of a pathogenic KCNH2 mutation on arrhythmia propensity in the two siblings with conotruncal defect. However, we remain cautious in excluding this possibility as the phenotypemay become apparent over time.

The prognostic impact of hyperglycemia on clinical outcomes of acute heart failure: Insights from the heart function assessment registry trial in Saudi Arabia

Background The prognostic impact of hyperglycemia (HG) in acute heart failure (AHF) is controversial. Our aim is to examine the impact of HG on short- and long-term survival in AHF patients. Methods Data from the Heart Function Assessment Registry Trial in Saudi Arabia (HEARTS) for patients who had available random blood sugar (RBS) were analyzed. The enrollment period was from October 2009 to December 2010. Comparisons were performed according to the RBS levels on admission as either <11.1 mmol/L or ≥11.1 mmol/L. Primary outcomes were hospital adverse events and short- and long-term mortality rates. Results A total of 2511 patients were analyzed. Of those, 728 (29%) had HG. Compared to non-HG patients, hyperglycemics had higher rates of hospital, 30-day, and 1-year mortality rates (8.8% vs. 5.6%; p = 0.003, 10.4% vs. 7.2%; p = 0.007, and 21.8% vs. 18.4%; p = 0.04, respectively). There were no differences between the two groups in 2- or 3-year mortality rates. After adjustment for relevant confounders, HG remained an independent predictor for hospital and 30-day mortality [odds ratio (OR) = 1.6; 95% confidence interval (CI) 1.07–2.42; p = 0.021, and OR = 1.55; 95% CI 1.07–2.25; p = 0.02, respectively]. Conclusion HG on admission is independently associated with hospital and short-term mortality in AHF patients. Future research should focus on examining the impact of tight glycemic control on outcomes of AHF patients.

Clinical Presentation, Predictors, and Outcomes Among Mineralocorticoid Receptor Antagonist (MRA)-Eligible Acute Heart Failure Patients in the Heart Function Assessment Registry Trial in Saudi Arabia (HEARTS)

Mineralocorticoid receptor antagonist (MRA) therapy is indicated after myocardial infarction in patients with acute heart failure (AHF) with an ejection fraction ≤40% and lacking contraindications. We analyzed clinical presentations, predictors, and outcomes of MRA-eligible patients within a prospective registry of patients with AHF from 18 hospitals in Saudi Arabia, from 2009 to 2010. For this subgroup, mortality rates were followed until 2013, and the clinical characteristics, management, predictors, and outcomes were compared between MRA-treated and non-MRA-treated patients. Of 2609 patients with AHF, 387 (14.8%) were MRA eligible, of which 146 (37.7%) were prescribed MRAs. Compared with non-MRA-treated patients, those prescribed MRAs more commonly exhibited non-ST-segment elevation myocardial infarction, acute on chronic heart failure, past history of ischemic heart disease, and severe left ventricular systolic dysfunction; were more commonly administered oral furosemide and digoxin; and had higher in-hospital recurrent congestive HF rates. Mortality did not significantly differ (P > .05) between groups. In Saudi Arabia, 37.7% of eligible patients received MRA treatment, which is higher than that in developed countries. The lack of long-term survival benefit raises concerns about systematic problems, for example, proper follow-up and management after hospital discharge, warranting further investigation.

Atrial Fibrillation in Patients Hospitalized With Heart Failure: Patient Characteristics and Outcomes From the HEARTS Registry

Effect of atrial fibrillation (AF) on short- and long-term outcomes in heart failure (HF) is controversial. Accordingly, we examined this relationship in a national multicenter project using data from the Hearts Function Assessment Registry Trial in Saudi Arabia that studied the clinical features and outcomes of patients admitted with de novo and acute on chronic HF. Out of 2593 patients with HF, 449 (17.8%) had AF at presentation. Patients with AF were more likely to be males and older (mean age 65.2 ± 15.0 vs 60.5 ± 14.8 years) to have a history of ventricular tachycardia/ventricular fibrillation (3.1% vs 1.9%) or cerebrovascular accident (15.0% vs 8.5%). However, they were less likely to have diabetes (66.0% vs 55.9%) or coronary artery disease (55.6% vs 42.3%). The 1-, 2-, and 3-year crude mortality rates were significantly higher in patients with AF (23.2% vs 18.3%, 27.4% vs 22.3%, and 27.8% vs 23.2%, respectively). However, there was no significant difference in mortality after adjusting for covariates. Thus, in patients admitted with HF, AF upon presentation was not associated with increased mortality.

Autosomal recessive long QT syndrome, type 1 in eight families from Saudi Arabia.

One of the most common primary cardiac arrhythmia syndromes is autosomal dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono‐allelic mutations in the KCNQ1 gene. Bi‐allelic mutations in the KCNQ1 gene are causal to Jervell and Lange‐Nielsen syndrome (JLNS), characterized by severe and early‐onset arrhythmias with prolonged QTc interval on surface ECG and sensorineural deafness. Occasionally, bi‐allelic mutations in KCNQ1 are also found in patients without any deafness, referred to as autosomal recessive long QT syndrome, type 1 (AR LQT1).