A novel homozygous SCN5A variant detected in sick sinus syndrome.

Sick sinus syndrome (SSS) is a group of disorders characterized by an abnormal cardiac impulse formation or propagation from the sinoatrial node. Mutated SCN5A has been reported in SSS, however, homozygosity of SCN5A is exceedingly rare. Here, we report a consanguineous family with four affected children with SSS. Symptomatic bradycardia necessitated implanting a pacemaker in all of them. Sequencing SCN5A revealed a novel homozygous variant (p.Cys1850Arg), which was predicted to interfere with protein folding. Our report describes the phenotype of a novel homozygous SCN5A variant and contributes to the compendium of molecular pathology of inherited arrhythmias in consanguineous populations.

Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.

BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.

New Insights into the Impact of Genome-Wide Copy Number Variations on Complex Congenital Heart Disease in Saudi Arabia.

Congenital heart diseases (CHDs) are complex traits that manifest in diverse clinical phenotypes such as the Tetralogy of Fallot (TOF), valvular and ventricular/atrial septal defects. Genetic mechanisms of CHDs have remained largely unclear to date. Copy number variations (CNVs) have been implicated in many complex diseases but their impact has not been examined extensively in various forms of CHD lesions. We report in this study, to the best of our knowledge, the largest cohort of Saudi Arab CHD patients to date who were evaluated using genome-wide CNV analysis. In a sample of 134 Saudi Arab patients with CHD, 66 exhibited pathogenic or likely pathogenic CNVs. Notably, 21 copy number gains and 11 copy number losses were detected that encompassed 141 genes and 146 genes, respectively. The most frequent gains were on 17q21.31, 8p11.21, and 22q11.23, whereas the losses were primarily localized to 16p11.2. Interestingly, all lesions have had gains at 17q21.31. Septal defects had also gains at 8p11.21 and 22q11.23, valvular lesions at 8p11.21, 22q11.23, and 2q13, and TOF at 16p11.2. Functional and network analyses demonstrated that cardiovascular and nervous system development and function as well as cell death/survival were most significantly associated with CNVs, thus highlighting the potentially important genes likely to be involved in CHD, including NPHP1, PLCB1, KANSL1, and NR3C1. In conclusion, this genome-wide analysis identifies a high frequency of CNVs mostly in patients with septal defects, primarily influencing cardiovascular developmental and functional pathways, thereby offering a deeper insight into the complex networks involved in CHD pathogenesis.

Effectiveness of Low to Moderate Physical Exercise Training on the Level of Low-Density Lipoproteins: A Systematic Review.

BACKGROUND: Regular exercise reduces risk factors associated with cardiovascular disease (CVD). Elevated low-density lipoprotein (LDL) contributes to atherosclerosis formation, which is associated with an increased risk of CVD. The relationship between exercise therapy and lipid levels has been widely studied, but it is established that high-intensity exercise improves lipid profile. However, the effectiveness of low- to moderate-intensity exercise in altering LDL levels is controversial. This review aims to identify the current evidence and existing gaps in literature in this area. METHODS: We searched and reviewed various randomized controlled clinical trials in the electronic databases EMBASE, CINAHL, the Web of Science, Cochrane, Pedro, Medline (PubMed), and Google Scholar using the keywords "low and moderate aerobic training," "exercise", "low-density lipoproteins," "cholesterol," "atherosclerosis," and "coronary artery diseases markers." We included studies that involved low- and/or moderate-intensity exercise training in apparently healthy adults over a period of 8 weeks and its effect on LDL levels. We selected a total of 11 studies from 469; nine were randomized controlled trials and two were systematic reviews. RESULTS: Aerobic exercise of both low and moderate intensity resulted in a significant reduction of total cholesterol. Effects on low-density lipoprotein levels were significant, and most of the studies showed changes in the level without significant relation to the type of exercise. At the same time, exercise improved the health status and physical fitness of all the participants in the included studies. CONCLUSION: This study found that low- and moderate-intensity exercise and low-density lipoprotein levels were not proven to be significantly related, except in a few studies that were limited to dyslipidemia population.

The phenotype, genotype, and outcome of infantile-onset Pompe disease in 18 Saudi patients.

Infantile-Onset Pompe Disease (IOPD) is an autosomal recessive disorder of glycogen metabolism resulting from deficiency of the lysosomal hydrolase acid α-glucosidase encoded by GAA gene. Affected infants present before the age of 12 months with hypotonia, muscle weakness, and hypertrophic cardiomyopathy. Enzyme replacement therapy (ERT) has been shown to improve survival, cardiac mass, and motor skills. In this work, we aim to illustrate the genotypes of IOPD and the outcome of ERT in our population. The medical records of infants with confirmed diagnosis of IOPD who received ERT were reviewed. Eighteen infants (7 males, 11 females) were included in the study. The median age at presentation was 2 months and the median age at the start of ERT was 4.5 months. Fifteen (83.3%) infants died with a median age at death of 12 months. The 3 alive infants (whose current ages are 6½â€¯years, 6 years, and 10 years), who were initiated on ERT at the age of 3 weeks, 5 months, and 8 months respectively, has had variable response with requirement of assisted ventilation in one child and tracheostomy in another child. All infants were homozygous for GAA mutations except one infant who was compound heterozygous. All infants (n = 8) with truncating mutations died. Our work provides insight into the correlation of genotypes and outcome of ERT in IOPD in Saudi Arabia. Our data suggest that early detection of cases, through newborn screening, and immunomodulation before the initiation of ERT may improve the outcome of ERT in Saudi infants with IOPD.