COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA

Background: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. Case presentation: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. Conclusions: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome. Keywords: COPA syndrome, Lung disease, Arthritis, Immune dysregulation, Case reportPeer Reviewe

The sequences of 150,119 genomes in the UK Biobank

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data(1,2). Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank(3). This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation

COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesBackground: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. Case presentation: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. Conclusions: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome

Molecular benchmarks of a SARS-CoV-2 epidemic.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadA pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland. We demonstrate how the viral concentration decreased in those newly diagnosed as the epidemic transitioned from exponential growth phase to containment phase. The viral concentration in the cases identified in population screening decreased faster than in those symptomatic and considered at high risk and that were targeted by the healthcare system. The viral concentration persists in recovering individuals as we found that half of the cases are still positive after two weeks. We demonstrate that accumulation of mutations in SARS-CoV-2 genome can be exploited to track the rate of new viral generations throughout the different phases of the epidemic, where the accumulation of mutations decreases as the transmission rate decreases in the containment phase. Overall, the molecular signatures of SARS-CoV-2 infections contain valuable epidemiological information that can be used to assess the effectiveness of containment measures

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Ron Clarke heads down the track with the Olympic torch, Melbourne Cricket Ground, 22 November, 1956 [picture] /

Part of the collection: Olympic Games, Melbourne, Victoria 1956.; Title devised by cataloguer from typed label on reverse.; Inscriptions: "Ron Clarke heads down the track with the Olympic torch, MCG. 22.11.1956"--Typed label on reverse.; Also available in electronic version via the Internet at: http//nla.gov.au/nla.pic-vn4278496-s44; Donated through the Australian Government's Cultural Gifts Program by Bruce Howard, 2007

Genetic variants associated with platelet count are predictive of human disease and physiological markers.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadPlatelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease

Spread of SARS-CoV-2 in the Icelandic Population.

To access publisher's full text version of this article click on the hyperlink belowContext: Radical cystectomy and pelvic lymph node dissection (RC and PLND) are an essential part of the treatment paradigm in high risk bladder cancer. However, these patients have high rates of morbidity and mortality related both to the treatment and to the disease.Objective: To provide overview of current literature about clinical markers that can be used to predict and improve BC-patient outcomes at the time of RC and PLND and to study if they are properly validated.Evidence acquisition: A systematic literature search was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria between January 1990 and October 2018 to identify English written original and review articles relevant to this topic. Prospective and retrospective studies were included.Evidence synthesis: There are several risk factors identified from non-randomised trials that can be improved before surgery to reduce perioperative mortality and morbidity. These include poor nutritional status, anaemia, renal function and smoking. Preoperative nomograms have also been developed to help decision-making and to inform patients about the risks of surgery. They can be used to estimate risk of postoperative mortality after RC and PLND with accuracy varying from 70 to 86%. These nomograms are largely based on retrospective data. Likewise, nomograms developed to calculate estimates about patient's overall and cancer specific survival have the same limitations.Conclusion: Clinical markers to predict morbidity, mortality and survival in patients with bladder cancer treated with RC and PLND may help to improve patient outcomes and treatment decision-making, but available data come from small retrospective trials and have not been properly validated. Prospective, multi-centre studies are needed to implement and disseminate predictive clinical markers and nomograms such that they can be utilised in treatment decision-making in daily practice.deCODE Genetics-Amge

Steam locomotive K107, holiday special passenger train arriving at Noojee Station, Noojee, Victoria, April 1935 [picture] /

Part of collection: Buckland collection of railway transport photographs.; Title devised by cataloguer based on inscription and other reference sources.; Inscriptions: "K 107 Noojee 4/35"--In blue ink on verso; "Photograph by John Buckland"--Stamp on verso.; Condition: Good.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn4196094