Burden of Mendelian disorders in a large Middle Eastern biobank

Background: Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies. Methods: Here, we interrogate 6045 whole genomes from Qatar—a Middle Eastern population with high consanguinity and understudied mutational burden—enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits. Results: We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1–3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region. Conclusions: This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.This study was, in part, financially supported by QGP, Qatar National Research Fund (QNRF award, QF-QBB-RES-PUB-003, NPRP10-1219-160035, NPRP10-0202-170320, and NPRP11S-0110-180250), as well as Sidra internal funds

Ritscher-Schinzel syndrome can be characterized as an endosomal recyclinopathy

Ritscher-Schinzel syndrome (RSS) is a congenital malformation syndrome characterized by cerebellar, cardiac, and craniofacial malformations and phenotypes associated with liver, skeletal, and kidney dysfunction. The genetic cause of RSS remains to be fully defined, and limited information is available regarding the root cause of the multiple tissue phenotypes. Causative mutations in the Commander multiprotein assembly are an emerging feature of this syndrome. Commander organizes the sorting nexin-17 (SNX17)-dependent recycling of hundreds of integral membrane proteins through the endosomal network. Here, we identify previously unrecognized cohorts of patients with RSS that we genetically and clinically analyzed to identify causative genes in the copper metabolic murr1 domain-containing (COMMD) proteins COMMD4, COMMD9, and coiled-coil domain containing 93 (CCDC93) subunits of the Commander complex. Using interactome analysis, we determined that these mutations disrupted Commander assembly and, through cell surface proteomics, that this reduces tissue-specific presentation of cell surface integral membrane proteins essential for kidney, bone, and brain development. We established that these integral proteins contained ΦxNPxY/F or ΦxNxxY/F sorting motifs in their cytoplasmic-facing domains (where Φ is a hydrophobic residue and x is any residue) that are recognized by SNX17 to drive their Commander-dependent endosomal recycling. Last, through generation of mouse models of RSS, we show replication of RSS-associated clinical phenotypes including proteinuria, skeletal malformation, and neurological impairment. Our data establish RSS as a "recyclinopathy" that arises from a dysfunction in the Commander endosomal recycling pathway

The third international hackathon for applying insights into large-scale genomic composition to use cases in a wide range of organisms

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Azerbaycan Türkiye ilişkileri (1992-2012) : bir dış politika bilançosu.

This study aims to examine the foreign policy of Azerbaijan toward Turkey in a historical perspective on the one hand and to analyze foreign policy formations during the Abulfaz Elchibey, Heydar Aliyev and Ilham Aliyev periods on the other. The thesis argues that One nation, two states principle does not have a validity in dictating the bilateral relations, instead a realist engagement is being favored by Azerbaijan with an emphasis on national interest. As a result, it is asserted that Azerbaijan’s foreign policy remains in a cautious and consistent manner toward Turkey.M.S. - Master of Scienc

Explaining the Diversity of Scrutiny Models. National Parliaments and the European Union: Baltic States in Comparative Perspective

A large and growing body of literature has investigated the national parliaments and their involvement in the activities of the Union. However, the literature does not fully cover all the national parliaments of new Member States which joined the EU after the largest enlargement of the Union in 2004. As well, little is known about the national parliaments of Baltic Member States. This paper aims to study the scrutiny models adopted by Baltic parliaments; it also seeks to address the question of ‗what factors do cause the differences in Baltic parliaments‘ scrutiny strategies?‘ Latvia, Lithuania and Estonia belong to the same group of countries and they have been the members of the European Union since 2004. Those countries have strong political, economic and cultural ties with similar size of population. It is interesting to learn how those three countries, which are very similar in most aspects, behave in different ways when it comes to parliamentary scrutiny of EU affairs. The analysis conducted in the research will based on prior studies of EU-15. Hence, the degree of influence of three explanatory variables is investigated in the study: 1) public support for membership; 2) party Euroscepticism; and 3) frequency of minority government

Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era

AbstractType 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The type 1 diabetes patient cohort is highly heterogeneous, with individuals presenting with disease at different stages and severities, arising from distinct etiologies, and overlaying varied genetic backgrounds. At present, the “one-size-fits-all” treatment for type 1 diabetes is exogenic insulin substitution therapy, but this approach fails to achieve optimal blood glucose control in many individuals. With advances in our understanding of early-stage diabetes development, diabetes stratification, and the role of genetics, type 1 diabetes is a promising candidate for a personalized medicine approach, which aims to apply “the right therapy at the right time, to the right patient”. In the case of type 1 diabetes, great efforts are now being focused on risk stratification for diabetes development to enable pre-clinical detection, and the application of treatments such as gene therapy, to prevent pancreatic destruction in a sub-set of patients. Alongside this, breakthroughs in stem cell therapies hold great promise for the regeneration of pancreatic tissues in some individuals. Here we review the recent initiatives in the field of personalized medicine for type 1 diabetes, including the latest discoveries in stem cell and gene therapy for the disease, and current obstacles that must be overcome before the dream of personalized medicine for all type 1 diabetes patients can be realized.</jats:p

Ethnic-specific association of amylase gene copy number with adiposity traits in a large Middle Eastern biobank

AbstractStudies assessing the impact of amylase genes copy number (CN) on adiposity report conflicting findings in different global populations, likely reflecting the impact of ancestral and ethnic-specific environment and lifestyle on selection at the amylase loci. Here, we leverage population size and detailed adiposity measures from a large population biobank to resolve confounding effects and determine the relationship between salivary (AMY1) and pancreatic (AMY2A) amylase genes CN and adiposity in 2935 Qatari individuals who underwent whole-genome sequencing (WGS) as part of the Qatar Genome Programme. We observe a negative association between AMY1 CNs and trunk fat percentage in the Qatari population (P = 7.50 × 10−3) and show that Qataris of Arab descent have significantly lower CN at AMY1 (P = 1.32 × 10−10) as well as less favorable adiposity and metabolic profiles (P &lt; 1.34 × 10−8) than Qataris with Persian ancestry. Indeed, lower AMY1 CN was associated with increased total and trunk fat percentages in Arabs (P &lt; 4.60 × 10−3) but not in Persians. Notably, overweight and obese Persians reported a significant trend towards dietary restraint following weight gain compared to Arabs (P = 4.29 × 10−5), with AMY1 CN showing negative association with dietary self-restraint (P = 3.22 × 10−3). This study reports an association between amylase gene CN and adiposity traits in a large Middle Eastern population. Importantly, we leverage rich biobank data to demonstrate that the strength of this association varies with ethnicity, and may be influenced by population-specific behaviors that also contribute to adiposity traits.</jats:p

1748-P: One Novel 7.2kb Deletion in Exon 8 of INSR Gene in Diabetic Qatari Female with Type A Insulin Resistance Syndrome: The 1000 Qatar-Omics Study Cohort

Background: A 46-year-old Qatari female with a BMI of 25kg/m2 presented with hyperglycemia (blood glucose 13.5 mmol/l), hyperinsulinemia (21µU/mL) with elevated levels of HbA1c (10.3mmol/l). Biochemical investigations showed raised serum C-peptide (2.02ng/ml) and triglycerides (2.07mmol/L) and uric acid (104mg/dL), with normal BP. The objective of this case study is to validate this variant found through WGS in insulin receptor (INSR) gene that play a major cause of insulin resistant syndrome with different spectrums. Methods: Structural Variants discovered using custom multi-algorithm pipeline developed and optimized to run on HPC for short-read WGS data. In brief, 10 software packages applied (Breakdancer, Breakseq2, CNVnator, Delly, ERDS, Genomestrip, Manta, Speedseq, Svaba, WHAM), to existing short-read data. SVs annotated using AnnotSV and provides us functionally, regulatory and clinically relevant information. SVs analyzed based on their properties like pli-score, overlaps with known databases and OMIM annotations. This deletion was validated by ddPCR and the molecular docking performed by the autodock suit in order to understand the effect of deletion in the interaction between this receptor and insulin. Results: The patient was identified with 7.2k heterozygous deletion in exon 8 of INSR gene which play an essential role in the formation of extracellular alpha subunits in insulin receptor. molecular docking proved the decrease of catalytic activity of INSR and, hence signaling. Considering this and the phenotypic data from Qatar biobank, the patient developed features of type A insulin resistant syndrome as consequence of persistence hyperinsulinemia. The patient also exhibits severe Deterioration of glucose tolerant even with medication and unfortunately developed nephropathy. Conclusion: We highlighted the power of NGS in precise diagnosis and developing a potential and promising targeted therapeutics. Disclosure A.S. Akil: None. E.A.M. Yassin: None. S. Subash Padmajeya: None. L.A. Jerman: None. A. Fadda: None. W.H.O. Aamer: None. E.E. Aliyev: None. K. Fakhro: None. </jats:sec