scholarly journals The Genomic Landscape of Pediatric Rheumatology Disorders in the Middle East

2020 ◽  
Author(s):  
Basil M Fathalla ◽  
Ali Alsarhan ◽  
Samina Afzal ◽  
Maha EL Naofal ◽  
Ahmad Abou Tayoun
Keyword(s):  
Middle East ◽  
United Arab Emirates ◽  
Diagnostic Yield ◽  
Periodic Fever ◽  
Copy Number Variants ◽  
Loss Of Function ◽  
Management Plans ◽  
Dual Diagnoses ◽  
Positive Rate ◽  
Gene Panels

AbstractGenetic investigations for patients with pediatric rheumatological disorders have been limited to classic genotyping testing, mainly MEFV hotspot mutation analysis, for periodic fever. Therefore, the landscape and clinical utility of comprehensive genomic investigations for a wider range of pediatric rheumatological disorders have not been fully characterized in the Middle East. Here seventy-one pediatric patients, of diverse Arab origins, were clinically and genetically assessed for a spectrum of rheumatology-related disease at the only dedicated tertiary children’s hospital in the United Arab Emirates. Clinical genomic investigations included mainly (76%) next generation sequencing-based gene panels and whole exome sequencing, along with rapid sequencing in the intensive care unit (ICU) and urgent setting. The overall positive yield was 46.5% (16.7%-66.7% for specific indications), while dual diagnoses were made in 2 cases (3%). Although the majority (21/33, 64%) of positive findings involved the MEFV gene, the remaining (12/33, 36%) alterations were attributed to eleven other genes/loci. Copy number variants contributed substantially (5/33, 15.2%) to the overall diagnostic yield. Sequencing-based testing, specifically rapid sequencing, had high positive rate and delivered timely results. Genetic findings guided clinical management plans and interventions in most cases (27/33, 81.8%). We highlight unique findings and provide additional evidence that heterozygous loss of function of the IFIH1 gene increases susceptibility to recurrent fevers. Our study highlights the importance of comprehensive genomic investigations in patients with pediatric rheumatological disorders, and provides new insights into the pathogenic variation landscape in this group of disorders.

scholarly journals Genetic heterogeneity of polymicrogyria: study of 123 patients using deep sequencing

2020 ◽  
Author(s):  
Chloe A Stutterd ◽  
Stefanie Brock ◽  
Katrien Stouffs ◽  
Miriam Fanjul-Fernandez ◽  
Paul J Lockhart ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
De Novo ◽  
Diagnostic Yield ◽  
Cortical Development ◽  
Copy Number Variants ◽  
Additional Patient ◽  
Cognitive Disability ◽  
Pathogenic Variants ◽  
Brain Malformations ◽  
Gene Panels

Abstract Polymicrogyria is a malformation of cortical development characterized by overfolding and abnormal lamination of the cerebral cortex. Manifestations include epilepsy, speech disturbance and motor and cognitive disability. Causes include acquired prenatal insults and inherited and de novo genetic variants. The proportion of patients with polymicrogyria and a causative germline or mosaic variant is not known. The aim of this study was to identify the monogenic causes of polymicrogyria in a heterogeneous cohort of patients reflective of specialized referral services. Patients with polymicrogyria were recruited from two clinical centres in Australia and Belgium. Patients with evidence of congenital cytomegalovirus infection or causative chromosomal copy number variants were excluded. One hundred and twenty-three patients were tested using deep sequencing gene panels including known and candidate genes for malformations of cortical development. Causative and potentially causative variants were identified and correlated with phenotypic features. Pathogenic or likely pathogenic variants were identified in 25/123 (20.3%) patients. A candidate variant was identified for an additional patient but could not be confirmed as de novo, and therefore it was classified as being of uncertain significance with high clinical relevance. Of the 22 dominant variants identified, 5 were mosaic with allele fractions less than 0.33 and the lowest allele fraction 0.09. The most common causative genes were TUBA1A and PIK3R2. The other eleven causative genes were PIK3CA, NEDD4L, COL4A1, COL4A2, GPSM2, GRIN2B, WDR62, TUBB3, TUBB2B, ACTG1 and FH. A genetic cause was more likely to be identified in the presence of an abnormal head size or additional brain malformations suggestive of a tubulinopathy, such as dysmorphic basal ganglia. A gene panel test provides greater sequencing depth and sensitivity for mosaic variants than whole exome or genome sequencing but is limited to the genes included, potentially missing variants in newly discovered genes. The diagnostic yield of 20.3% indicates that polymicrogyria may be associated with genes not yet known to be associated with brain malformations, brain-specific somatic mutations or non-genetic causes.

scholarly journals Systematic evaluation of genome sequencing as a first-tier diagnostic test for prenatal and pediatric disorders

2020 ◽  
Author(s):  
Chelsea Lowther ◽  
Elise Valkanas ◽  
Jessica L. Giordano ◽  
Harold Z. Wang ◽  
Benjamin B. Currall ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Chromosomal Abnormalities ◽  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Added Value ◽  
Systematic Evaluation ◽  
Single Nucleotide Variants ◽  
Sensitivity Specificity ◽  
Gene Panels

ABSTRACTCurrent prenatal and pediatric genetic evaluation requires three tests to capture balanced chromosomal abnormalities (karyotype), copy number variants (microarray), and coding variants (whole exome sequencing [WES] or targeted gene panels). Here, we explored the sensitivity, specificity, and added value of whole genome sequencing (WGS) to displace all three conventional approaches. We analyzed single nucleotide variants, small insertions and deletions, and structural variants from WGS in 1,612 autism spectrum disorder (ASD) quartet families (n=6,448 individuals) to benchmark the diagnostic performance of WGS against microarray and WES. We then applied these WGS variant discovery and interpretation pipelines to 175 trios (n=525 individuals) with a fetal structural anomaly (FSA) detected on ultrasound and pre-screened by karyotype and microarray. Analyses of WGS in ASD quartets identified a diagnostic variant in 7.5% of ASD probands compared to 1.1% of unaffected siblings (odds ratio=7.5; 95% confidence interval=4.5-13.6; P=2.8×10−21). We found that WGS captured all diagnostic variants detected by microarray and WES as well as five additional diagnoses, reflecting a 0.3% added yield over WES and microarray when combined. The WGS diagnostic yield was also inversely correlated with ASD proband IQ. Implementation in FSA trios identified a diagnostic variant not captured by karyotype or microarray in 12.0% of fetuses. Based on these data and prior studies, we estimate that WGS could provide an overall diagnostic yield of 47.6% in unscreened FSA referrals. We observed that WGS was sensitive to the detection of all classes of pathogenic variation captured by three conventional tests. Moreover, diagnostic yields from WGS were superior to any individual genetic test, warranting further evaluation as a first-tier diagnostic approach.

scholarly journals Genetic architecture of schizophrenia: a review of major advancements

2021 ◽  
pp. 1-10
Author(s):  
Sophie E. Legge ◽  
Marcos L. Santoro ◽  
Sathish Periyasamy ◽  
Adeniran Okewole ◽  
Arsalan Arsalan ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Association Studies ◽  
Copy Number Variants ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Loci ◽  
Significant Enrichment ◽  
High Heritability ◽  
Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2021 ◽  
Author(s):  
Stephen E. Lincoln ◽  
Tina Hambuch ◽  
Justin M. Zook ◽  
Sara L. Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
Next Generation Sequencing Ngs ◽  
The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

scholarly journals Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2704
Author(s):  
Sally Yepes ◽  
Nirav N. Shah ◽  
Jiwei Bai ◽  
Hela Koka ◽  
Chuzhong Li ◽  
...  
Keyword(s):  
Internal Control ◽  
Susceptibility Gene ◽  
Copy Number Variants ◽  
Bone Cancer ◽  
Chinese Patients ◽  
European Ancestry ◽  
Unknown Etiology ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Pathogenic Variants

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

scholarly journals 1293. Sulbactam-durlobactam is active against recent, multi-drug resistant Acinetobacter baumannii clinical isolates from the Middle East

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S662-S662
Author(s):  
Alita Miller ◽  
Sarah McLeod ◽  
Samir Moussa ◽  
Meredith Hackel
Keyword(s):  
Antibacterial Activity ◽  
Middle East ◽  
Acinetobacter Baumannii ◽  
United Arab Emirates ◽  
Blood Stream ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Surveillance Systems ◽  
Spectrum Activity

Abstract Background The incidence of infections caused by multidrug-resistant (MDR) Acinetobacter baumannii (Ab) is increasing at an alarming rate in certain regions of the world, including the Middle East. Sulbactam (SUL) has intrinsic antibacterial activity against Ab; however, the prevalence of β-lactamases in Ab has limited its therapeutic utility. Durlobactam (DUR, formerly ETX2514) is a diazabicyclooctenone β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases that restores SUL activity in vitro against MDR Ab. SUL-DUR is an antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug-resistant strains, that is currently in Phase 3 clinical development. In global surveillance studies of >3600 isolates from 2012-2017, the MIC90 of SUL-DUR was 2 mg/L. Although surveillance systems to monitor MDR infections in the Middle East are currently being established, quantitative, prevalence-based data are not yet available. Therefore, the potency of SUL-DUR was determined against 190 recent, diverse Ab clinical isolates from this region. Methods 190 Ab isolates were collected between 2016 - 2018 from medical centers located in Israel (N = 47), Jordan (N = 36), Qatar (N = 13), Kuwait (N = 42), Lebanon (N = 8), Saudi Arabia (N = 24) and United Arab Emirates (N = 20). Seventy-five percent and 20.5% of these isolates were from respiratory and blood stream infections, respectively. Susceptibility to SUL-DUR and comparator agents was performed according to CLSI guidelines, and data analysis was performed using CLSI and EUCAST breakpoint criteria where available. Results This collection of isolates was 86% carbapenem-resistant and 90% sulbactam-resistant (based on a breakpoint of 4 mg/L). The addition of SUL-DUR (fixed at 4 mg/L) decreased the sulbactam MIC90 from 64 mg/L to 4 mg/L. Only 3 isolates (1.6%) had SUL-DUR MIC values of > 4 mg/L. This potency was consistent across countries, sources of infection and subsets of resistance phenotypes. Conclusion SUL-DUR demonstrated potent antibacterial activity against recent clinical isolates of Ab from the Middle East, including MDR isolates. These data support the global development of SUL-DUR for the treatment of MDR Ab infections. Disclosures Alita Miller, PhD, Entasis Therapeutics (Employee) Sarah McLeod, PhD, Entasis Therapeutics (Employee) Samir Moussa, PhD, Entasis Therapeutics (Employee)

scholarly journals May Measurement Month 2017: an analysis of blood pressure screening results from the United Arab Emirates—Northern Africa and Middle East

2019 ◽  
Vol 21 (Supplement_D) ◽  
pp. D118-D120 ◽  
Author(s):  
Afzalhussein Yusufali ◽  
Nooshin Bazargani ◽  
Amrish Agrawal ◽  
Khalifa Muhammed ◽  
Hanan Obaid ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Middle East ◽  
United Arab Emirates ◽  
Northern Africa ◽  
Blood Pressure Screening

scholarly journals Limited Genetic Diversity Detected in Middle East Respiratory Syndrome-Related Coronavirus Variants Circulating in Dromedary Camels in Jordan

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 592
Author(s):  
Stephanie N. Seifert ◽  
Jonathan E. Schulz ◽  
Stacy Ricklefs ◽  
Michael Letko ◽  
Elangeni Yabba ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Middle East ◽  
United Arab Emirates ◽  
Sequence Data ◽  
Case Fatality ◽  
High Sensitivity ◽  
Middle East Respiratory Syndrome ◽  
Full Genome Sequence ◽  
Genome Sequences ◽  
Dromedary Camels

Middle East respiratory syndrome-related coronavirus (MERS-CoV) is a persistent zoonotic pathogen with frequent spillover from dromedary camels to humans in the Arabian Peninsula, resulting in limited outbreaks of MERS with a high case-fatality rate. Full genome sequence data from camel-derived MERS-CoV variants show diverse lineages circulating in domestic camels with frequent recombination. More than 90% of the available full MERS-CoV genome sequences derived from camels are from just two countries, the Kingdom of Saudi Arabia (KSA) and United Arab Emirates (UAE). In this study, we employ a novel method to amplify and sequence the partial MERS-CoV genome with high sensitivity from nasal swabs of infected camels. We recovered more than 99% of the MERS-CoV genome from field-collected samples with greater than 500 TCID50 equivalent per nasal swab from camel herds sampled in Jordan in May 2016. Our subsequent analyses of 14 camel-derived MERS-CoV genomes show a striking lack of genetic diversity circulating in Jordan camels relative to MERS-CoV genome sequences derived from large camel markets in KSA and UAE. The low genetic diversity detected in Jordan camels during our study is consistent with a lack of endemic circulation in these camel herds and reflective of data from MERS outbreaks in humans dominated by nosocomial transmission following a single introduction as reported during the 2015 MERS outbreak in South Korea. Our data suggest transmission of MERS-CoV among two camel herds in Jordan in 2016 following a single introduction event.

scholarly journals Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

2021 ◽  
Vol 22 (12) ◽  
pp. 6410
Author(s):  
Vasily Smirnov ◽  
Olivier Grunewald ◽  
Jean Muller ◽  
Christina Zeitz ◽  
Carolin D. Obermaier ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Copy Number Variants ◽  
Cone Dystrophy ◽  
The Novel ◽  
Targeted Next Generation Sequencing ◽  
Large Deletions ◽  
Gene Panels ◽  
Generation Sequencing

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

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