We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.
Non-alcoholic fatty liver disease (NAFLD) is a progressive disease that encompasses a spectrum of liver diseases, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Data related to survival in children are scarce, but these data firmly associate NAFLD with higher risks of hepatic and non-hepatic morbidities and mortalities compared with the general population. More recently, the association between NAFLD and cardiovascular disease among children has increasingly been recognized. Given that obesity is a major risk factor for the disease, paediatric NAFLD is becoming a global issue, paralleling the dramatic rise in obesity worldwide. NASH, which is more common in obese children, has the potential to advance to liver fibrosis and failure. It is unclear why certain patients undergo such transformation but this susceptibility is likely related to an interaction between a genetically susceptible host and the surrounding environment. Currently, treatment is largely conservative and includes lifestyle modification, attainable through healthy weight reduction via diet and exercise. In this review, current knowledge about NAFLD in children is summarized. This review aims to increase the awareness of the medical community about a hidden public health issue and to identify current gaps in the literature while providing directions for future research.
BackgroundPrimary immunodeficiency disorders associated with autoimmunity are poorly understood. Central nervous system (CNS) vasculitis can complicate the courses of such entities, but it is underappreciated. Deletion of the dedicator of cytokinesis 8 (DOCK8) gene is considered to be the autosomal recessive form of hyperimmunoglobulin E syndrome which is a rare type of primary immunodeficiency disease characterized by elevated levels of IgE antibody, eczema, and recurrent staphylococcal infections. DOCK8 deletion is associated with fatal CNS vasculitis. However, descriptions of such cases and their outcomes are scarce in the literature.Case presentationThis report describes a young female with a DOCK8 gene deletion presenting acutely with squint, fatigue and visual hallucinations. The patient was diagnosed as having neuritis of the third oculomotor nerve and encephalitis, which were thought to be related to her underlying immune deficiency, however, she subsequently was diagnosed with CNS vasculitis based on brain magnetic imaging and magnetic resonance angiography findings. We provide here a comprehensive description of the patient’s clinical outcome and outline an effective treatment approach that may be useful for similar patients and includes the use of steroids and mycophenolate mofetil (MMF). The treatment was well tolerated and enabled the patient to recover most of her neurological deficits. However, despite the initial improvement, she later developed stroke.ConclusionsTo the best of our knowledge, this is the first report in the literature of a case of primary immunodeficiency complicated by CNS vasculitis demonstrating a successful outcome. Our observations indicate that the combination of MMF and steroids is an effective treatment for CNS vasculitis associated with DOCK8 deficiency. However, lack of awareness of the neurological comorbidities associated with primary immunodeficiencies and the delay in diagnosis likely contributed to the development of acute cerebral infarction. Early treatment and aggressive control of the disease’s initial inflammation is essential for preventing catastrophic stroke.
Background: Bronchial asthma is a chronic inflammatory airway disease that is characterized by reversible airway obstruction due to bronchial hyperresponsiveness. It is one of the most common chronic diseases. In Saudi Arabia, asthma affects 2 million people with asthma frequency in children markedly higher than adults with regional variations ranging from 9% to 33.7%. Objective: The aim of this study is to measure asthma awareness and knowledge of study participants during the ongoing annual Saudi asthma awareness campaigns and compare them with previous survey data conducted in 2014. Methods: A cross-sectional study was carried out in the form of a survey distributed across three major cities in Saudi Arabia, Jeddah, Riyadh and Dammam, during the National Asthma Awareness Campaign in major regional shopping centers in April 2019. Asthma knowledge scores across different demographic groups were generated from surveyed data. Descriptive and correlative statistical analyses were performed to identify factors associated with changes in asthma knowledge. Scores were compared to previous survey results. Results: The mean score for asthma knowledge was 15.6 out of 25. Asthma knowledge significantly correlated with age (P=0.002), asthma status of the participants (P=0.001), having children with asthma (P=0.005) or knowing friends or family with asthma (P=0.029) but not with other socioeconomic factors such as gender, marital status, occupation, level of education and number of children in the family (P > 0.05). There was a significant difference in the asthma scores from 2014 (M= 63%, SD=26) to 2019 (M= 70%, SD= 26) conditions; t (24) = −2.106, p=0.046. Conclusion: Further educational campaigns are necessary to enhance and measure general public awareness of asthma, its differential diagnosis against other respiratory infections, environmental triggers, risk factors as well as treatment options.
The crosstalk between host immunity and the external environment in the mucous membranes of the gastrointestinal and respiratory tracts in bronchial asthma has recently been scrutinized. There is compelling evidence that the microbiota at these sites may play an important role in the pathogenesis of this chronic airway disease. The appearance of bacteria early in life in the gut before dissemination to the airways plays a pivotal role in shaping mucosal immunity. Loss of microbial diversity or dysbiosis can result in aberrant immunemediated inflammation and mucosal barrier disruption, which coincides clinically with the successive development of the "allergic march" in asthma. Microbial manipulation may be effective in curbing asthma development by indirectly preserving homeostatic epithelial barrier functions. The protective effects and mechanisms of immunity-microbiome crosstalk at mucosal sites require further investigation to identify therapeutic and preventive measures in asthma. This topical review aims to highlight new evidence that compromised epithelial barrier function, which results in deregulated crosstalk between the microbiome and host mucosal immune system, is an important disease mechanism in asthma. In the light of current COVID-19 pandemic, the collective findings on the impact of mucosal microbiota on the suceptibility to SARS-CoV-2 infection and severity of COVID-19 is explored. The possible therapeutic implications to target these abnormalities are further discussed.
Purpose Guidelines for managing neonatal hemolytic disease of the newborn (HDN) recommend a selective approach in the use of direct antiglobulin test (DAT). In Saudi Arabia, many hospitals still perform routine DAT for all newborns. This study assessed the need for phototherapy in relation to DAT results in full-term healthy newborns. Patients and Methods A retrospective analysis of all healthy newborns admitted during 2018 was performed. The primary outcome was the association of positive DAT results with phototherapy. Results There were 1463 newborns born during the study period. The DAT was positive at 4.4%. The 24-hour bilirubin levels were higher in DAT-positive cases ( P =0.06); however, peak bilirubin levels were not correlated with the DAT results ( P =0.717). Thirty-six neonates (2.46%) required phototherapy, and the need was similar among DAT-positive and DAT-negative cases ( P =0.271). The most common indication for phototherapy was clinical jaundice in 22 neonates (61.1%), followed by DAT positivity in 12 (33.3%) and hospital protocol in 2 patients (5.6%) ( P <0.01 by chi-square overall comparison). Conclusion Our results indicate that factors other than DAT positivity are important in assessing the need for phototherapy in newborns. Clinical signs of jaundice were indicators of high serum bilirubin levels and subsequent phototherapy, further indicating that the DAT test was overused in predicting the need for phototherapy.
BackgroundChronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease primarily presents with recurrent infections, and patients may also present with inflammatory conditions, including noninfectious colitis, and an increased frequency of autoimmunity. We report here a patient with CGD in whom the presentation, unlike the classical presentation of CGD, was predominantly of an inflammatory and autoimmune phenotype.Case presentationA 3-year-old Pakistani female presented with bloody diarrhea since the age of 7 days, followed by the development of perianal abscesses and fistula. There was no other history of recurrent infections. The patient subsequently developed joint pain and stiffness with persistently elevated inflammatory markers and elevated anti-cyclic citrullinate peptide (anti-CCP) antibody titer. She was diagnosed with oligoarticular juvenile idiopathic arthritis and colitis. The diagnosis of CGD was later made and was based on the absence of NADPH oxidase activity in the patient’s neutrophils upon phorbol myristate acetate (PMA) stimulation using the dihydrorhodamine-1,2,3 (DHR) flow cytometry test. Targeted next-generation sequencing revealed an unreported deletion mutation in exon 10 as a homozygous loss-of-function variant of the human neutrophil oxidase factor 2 (NCF2) (NCF2: NM_001190789, nucleotide change: c.855_856del:p.T285fs). The gene encodes a protein subunit, p67phox, in the NADPH enzyme complex.ConclusionsThe case emphasizes the importance of maintaining high clinical suspicion of immunodeficiency and CGD in patients with very-early-onset colitis and autoimmune disorders. This case is important due to its rarity and because it might represent a previously undiscovered mutation, which is possibly more common in the patient’s ethnic group. Other mutations in NCF2 have been linked to inflammatory bowel disease and autoimmunity, but without CGD, suggesting similarities in the pathogenesis.
Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder (PID) affecting NADPH oxidase activity. The rarest form of the disease is considered to be caused by NCF2 gene bi‐allelic variant. Here, we report the clinical and molecular characterization of a patient presenting with early‐onset severe disease due to bi‐allelic NCF2 variant. Methods Gene mutational analysis was performed by whole‐exome and Sanger sequencing. Results The patient presented with a history of fever and rash since the age of 1 month, followed by destructive osteomyelitis and necrotizing lymphadenopathy. The patient received the Bacillus Calmette‐Guérin (BCG) vaccine at birth; she was subsequently diagnosed with disseminated BCG infection. Whole‐exome sequencing identified a private (unreported) homozygous variant in NCF2 (c.290C > A) that results in a nonconservative change, p.Ala97Asp, in the p67phox protein. The variant is located in the third helix of the TRP domain, which is crucial for the binding of GTPase RAC2 to the NADPH oxidase complex. Conclusion We identified a novel NCF2 variant located in the region interacting with RAC2 that is linked to a severe and early CGD phenotype in the setting of disseminated BCG infection. Our findings support postponing BCG vaccination until 6–12 months of age and after PID assessment.
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