A Study on the Genetics of Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a poorly understood disorder. It is primarily autosomal recessive and is prevalent in tribal communities of the United Arab Emirates due to consanguineous marriages. This retrospective study aimed to assess the pathogenicity of the genetic variants of PCD in indigenous patients with significant clinical respiratory problems. Pathogenicity scores of variants obtained from the chart review were consolidated using the Ensembl Variant Effect Predictor. The multidimensional dataset of scores was clustered into three groups based on their pathogenicity. Sequence alignment and the Jensen-Shannon Divergence (JSD) were generated to evaluate the amino acid conservation at the site of the variation. One-hundred and twelve variants of 28 genes linked to PCD were identified in 66 patients. Twenty-two variants were double heterozygous, two triple heterozygous, and seven homozygous. Of the thirteen novel variants, two, c.11839 + 1G > A in dynein, axonemal, heavy chain 11 (DNAH11) and p.Lys92Trpfs in dynein, axonemal, intermediate chain 1 (DNAI1) were associated with dextrocardia with situs inversus, and one, p.Gly21Val in coiled-coil domain-containing protein 40 (CCDC40), with absent inner dynein arms. Homozygous C1orf127:p.Arg113Ter (rs558323413) was also associated with laterality defects in two related patients. The majority of variants were missense involving conserved residues with a median JSD score of 0.747. Homology models of two deleterious variants in the stalk of DNAH11, p.Gly3102Asp and p.Leu3127Arg, revealed structural importance of the conserved glycine and leucine. These results define potentially damaging PCD variants in the region. Future studies, however, are needed to fully comprehend the genetic underpinnings of PCD.

Genetic variants of small airways and interstitial pulmonary disease in children.

Genetic variants of small airways and interstitial pulmonary disease have not been comprehensively studied. This cluster of respiratory disorders usually manifests from early infancy ('lung disease in utero'). In this study, 24 variants linked to these entities are described. The variants involved two genes associated with surfactant metabolism dysfunction (ABCA3 and CSF2RB), two with pulmonary fibrosis (MUC5B and SFTP), one with bronchiectasis (SCNN1B), and one with alpha-1-antitrypsin deficiency (SERPINA1). A nonsense variant, MUC5B:c.16861G > T, p.Glu5621*, was found in homozygous state in two siblings with severe respiratory disease from birth. One of the siblings also had heterozygous SFTPA1:c.675C > G, p.Asn225Lys, which resulted in a more severe respiratory disease. The sibling with only the homozygous MUC5B variant had lung biopsy, which showed alveolar simplification, interstitial fibrosis, intra-alveolar lipid-laden macrophages, and foci of foreign body giant cell reaction in distal airspaces. Two missense variants, MUC5B:c.14936 T > C, p.Ile4979Thr (rs201287218) and MUC5B:c.16738G > A, p.Gly5580Arg (rs776709402), were also found in compound heterozygous state in two siblings with severe respiratory disease from birth. Overall, the results emphasize the need for genetic studies for patients with complex respiratory problems. Identifying pathogenic variants, such as those presented here, assists in effective family counseling aimed at genetic prevention. In addition, results of genetic studies improve the clinical care and provide opportunities for participating in clinical trials, such as those involving molecularly-targeted therapies.

Genetic variants in children with chronic respiratory diseases.

Founder mutations and autosomal recessive (AR) disorders are common in the Arabian Peninsula due to frequent consanguineous marriages. As a result, the pulmonary service at Tawam Hospital (Al Ain, UAE) routinely requests genetic testing for children with persistent (unexplained) respiratory problems. The main purpose of this report was to underscore the usefulness of these tests. Ten children with severe respiratory diseases due to complex genetic findings are described here. Forty-one variants (six novel) were detected, averaging four per patient (range: 1-9). Seven (17%) variants were homozygous and 34 (83%) heterozygous; some variants were known to show monoallelic expression. Using binomial probability distribution, the fetal-risk for having AR disorder(s) as a function of the number of shared variants by a couple ranged from 0.25 (having one shared variant) to 0.9249 (having nine shared variants). In cultures where increased size of homozygous genomic segments is common, children often have multiple variants that could cause complex clinical phenotypes. Identifying pathogenic variants assists in clinical care, family counseling, and disease prevention through genetic screening.

Cross-sectional study assessing the performance of the Arabic translated childhood asthma control test.

The standard Arabic version of the Childhood Asthma Control Test (C-ACT) has never been previously evaluated in Arab countries. We studied its correlation in Arabic speaking children in the United Arab Emirates (UAE), with both the GINA assessment of asthma control and the resulting changes in asthma management. The Arabic C-ACT was completed by the children or by their parents when needed. A GINA based level of asthma control score was assigned by their managing physician. The correlation between the different cut- scores of the C-ACT and GINA were studied. A total of 105 eligible children with asthma (aged between 4 and 11.8 years, 61% boys) were enrolled. The Arabic translated C-ACT had a high reliability (Cronbach alpha 81%) and validity (as it correlated well with the GINA level of control). We found that using it with the traditional cut-score of 19 overestimated the degree of asthma control. Instead, a calculated optimal cut-score of 20 estimated more accurately the level of asthma control as assessed both by the GINA assessment and also by changes in asthma management. The current Arabic version of the C-ACT has a good reliability and validity. By using a single optimal cut-point of 20, it can be used to assess both the level of asthma control and of treatment control. It does not, however, accurately define asthma control when using the originally proposed cut-score of 19. Physicians need to recognise that the C-ACT cut-points may vary in different populations. We suggest that cut-scores of translated versions need to be modified in different geographical settings.

Nasopharyngeal isolates and their clinical impact on young children with asthma: a pilot study.

INTRODUCTION: Respiratory infections have significant effects on childhood asthma. Viral respiratory infections, such as rhinovirus and respiratory syncytial virus are likely to be important in the development and exacerbation of asthma. In this study, we investigated the nasopharyngeal colonization in children with asthma to determine the prevalence of pathogens and their contribution to respiratory symptoms and airway resistance during winter. METHODS: From December 2016 to March 2017, 50 nasopharyngeal specimens were collected from 18 patients (age, 5.0±1.1 years) with asthma and 9 specimens from 9 control children (age, 4.9±1.0 years). Samples were tested for 19 viruses and 7 bacteria, using multiplex real-time PCR. Respiratory disease markers included the Global Asthma Network Questionnaire, the Common-Cold Questionnaire, the Global Initiative for Asthma assessment of asthma control, and the airway resistance at 5 Hz by forced-oscillation technique. RESULTS: The most commonly isolated organisms in both groups (patients and controls) were Streptococcus pneumoniae, Haemophilus influenzae, and rhinovirus. Most patients had multiple isolates (median, 3.5; range, 1-5), which changed during the study period. Types of isolates were 4 bacteria (S. pneumoniae, H. influenzae, Bordetella pertussis, and Bordetella parapertussis) and 6 viruses (rhinovirus, enterovirus, metapneumovirus, adenovirus, coronaviruses, and parainfluenza viruses). Similar isolates, including influenza A-H3 virus and bocavirus, were detected in the controls. Of the 9 patients with "wheezing disturbing sleep ≥1 per week", 6 had rhinovirus, 2 coronaviruses, and 1 no detectable viruses. Patients with mild common cold symptoms had significantly higher airway resistance at 5 Hz z-score (P=0.025). CONCLUSION: Multiple respiratory pathogens were isolated from many patients with asthma, which appeared to contribute to disease symptoms and airway resistance. Minimizing children's exposure to respiratory pathogens might be beneficial, especially during winter.

Respiratory function in healthy Emirati children using forced oscillations.

BACKGROUND: The forced oscillation technique (FOT) allows the quantification of respiratory function, does not require active cooperation and as such is ideally suited for use in young children. The application of the FOT in non-Caucasian populations is limited and it remains unclear if current reference ranges for the FOT in Caucasian children are appropriate for children in the Arabian Peninsula. This study explored the use of the FOT in healthy school-aged children in the United Arab Emirates (UAE). METHODS: Lung function using FOT was assessed in healthy Emirati children aged 4-12 years. Using a validated questionnaires general medical and respiratory histories were obtained. Prediction equations for resistance (Rrs), reactance (Xrs), and area under reactance curve (AX) were calculated and compared to previous studies. RESULTS: FOT was successfully obtained in 291 healthy Emirati children. Linear regression modelling including weight, height, age, and gender in transformed FOT outcomes demonstrated that height was the strongest predictor of FOT outcomes (P < 0.001). Using the equated prediction equation Z-scores were calculated. FOT outcomes in Emirati children did not match previously published reference equations in Caucasians children (P < 0.001). CONCLUSION: FOT measurements were feasible in Emirati school-children. New FOT reference equation in Emirati children were derived. FOT reference equation in Emirati children was different from published equations in Caucasians.

Is forced oscillation technique the next respiratory function test of choice in childhood asthma.

Respiratory diseases, especially asthma, are common in children. While spirometry contributes to asthma diagnosis and management in older children, it has a limited role in younger children whom are often unable to perform forced expiratory manoeuvre. The development of novel diagnostic methods which require minimal effort, such as forced oscillation technique (FOT) is, therefore, a welcome and promising addition. FOT involves applying external, small amplitude oscillations to the respiratory system during tidal breathing. Therefore, it requires minimal effort and cooperation. The FOT has the potential to facilitate asthma diagnosis and management in pre-school children by faciliting the objective measurement of baseline lung function and airway reactivity in children unable to successfully perform spirometry. Traditionally the use of FOT was limited to specialised centres. However, the availability of commercial equipment resulted in its use both in research and in clinical practice. In this article, we review the available literature on the use of FOT in childhood asthma. The technical aspects of FOT are described followed by a discussion of its practical aspects in the clinical field including the measurement of baseline lung function and associated reference ranges, bronchodilator responsiveness and bronchial hyper-responsiveness. We also highlight the difficulties and limitations that might be encountered and future research directions.