Identity-by-Descent Analysis Uncovering a Founder Event in a Novel Hereditary Small Vessel Cerebral Disease.

Background: A novel genetic cerebral small vessel disease, linked to the insertion of a mobile genetic element in the gene has recently been identified. Notably, 8 out of the 10 families carrying this mutation were known to come from Brittany, a specific region in France, suggesting the possibility of a common ancestor and a founder effect.

Methods: Probands from each of the 10 families were analyzed with high-density single nucleotide polymorphism arrays.

Exome Sequencing of Fetuses With Intracranial Hemorrhage Unravels Novel Causative Genes and an Extreme Genetic Heterogeneity.

Objective: Fetal intracranial hemorrhage (FICH) is a rare and potentially deleterious condition. Fetal alloimmune thrombocytopenia and pathogenic variations in COL4A1/A2 genes are well-recognized causes of FICH. However, pathogenic COL4A1/A2 variations are identified in only 20% of fetuses referred for FICH after excluding other known causes, leaving the majority unexplained and making genetic counseling difficult.

An AluYa5 Insertion in the 3'UTR of COL4A1 and Cerebral Small Vessel Disease.

Importance: Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes.

Objective: To identify novel genes and mechanisms associated with familial CSVD.

Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease.

Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands).

Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating Variations.

Objectives: To refine the clinical spectrum of a very recently identified phenotype associated with end-truncating pathogenic variations.

Methods: Detailed clinical, neuropsychological, and MRI investigation of 6 patients from 2 unrelated families segregating end-truncating variations.

Results: All patients harbored end-truncating pathogenic variation.

Biallelic variants in NOS3 and GUCY1A3, the two major genes of the nitric oxide pathway, cause moyamoya cerebral angiopathy.

Background: Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA.

RAVAQ: An integrative pipeline from quality control to region-based rare variant association analysis.

Next-generation sequencing technologies have opened up the possibility to sequence large samples of cases and controls to test for association with rare variants. To limit cost and increase sample sizes, data from controls could be used in multiple studies and might thus be generated on different sequencing platforms. This could pose some problems of comparability between cases and controls due to batch effects that could be confounding factors, leading to false-positive association signals.

COL4A1/COL4A2 and inherited platelet disorder gene variants in fetuses showing intracranial hemorrhage.

Background: Variants of COL4A1/COL4A2 genes have been reported in fetal intracranial hemorrhage (ICH) cases but their prevalence and characteristics have not been established in a large series of fetuses. Fetal neonatal alloimmune thrombocytopenia is a major acquired ICH factor but the prevalence and characteristics of inherited platelet disorder (IPD) gene variants leading to thrombocytopenia are unknown. Herein, we screened COL4A1/COL4A2 and IPD genes in a large series of ICH fetuses.

End-Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy.

Objective: The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes.

Methods: We performed a gene-based collapsing test of rare protein-truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large-scale databases, gnomAD and TOPMed.

On the nonlinear effects of energy consumption, economic growth, and tourism on carbon footprints in the USA.

The present paper implements the quantile autoregressive lagged (QARDL) approach of Cho et al. (2015) and the Granger causality in quantiles tests of Troster et al. (2018) to explore the nonlinear effects of US energy consumption, economic growth, and tourist arrivals on carbon dioxide (CO) emission.

COVID-19 pandemic, oil prices, stock market, geopolitical risk and policy uncertainty nexus in the US economy: Fresh evidence from the wavelet-based approach.

In this paper, we analyze the connectedness between the recent spread of COVID-19, oil price volatility shock, the stock market, geopolitical risk and economic policy uncertainty in the US within a time-frequency framework. The coherence wavelet method and the wavelet-based Granger causality tests applied to US recent daily data unveil the unprecedented impact of COVID-19 and oil price shocks on the geopolitical risk levels, economic policy uncertainty and stock market volatility over the low frequency bands. The effect of the COVID-19 on the geopolitical risk substantially higher than on the US economic uncertainty.

Dysregulated pathways and differentially expressed proteins associated with adverse transfusion reactions in different types of platelet components.

Platelet components (PCs) are occasionally associated with adverse transfusion reactions (ATRs). ATRs can occur regardless of the type of PC being transfused, whether it is a single-donor apheresis PC (SDA-PC) or a pooled PC (PPCs). The purpose of this study was to investigate the proteins and dysregulated pathways in both of the main types of PCs.

Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome.

Background: The molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients.

Objective: This study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya.

Methods: Rare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data.

Data from differentially expressed proteins in platelet components associated with adverse transfusion reactions.

The presented dataset was used for the study focused on the search for differentially expressed proteins in blood platelet components (PCs) associated with adverse transfusion reactions (ATRs). Pellets of ATR platelet components and their controls were subjected to high-throughput proteomics analysis using a Q Exactive high-resolution tandem mass spectrometer. The data reported here constitutes an extension of "Differential protein expression of blood platelet components associated with adverse transfusion reactions" article Aloui et al.

Clinical and Molecular Features of 5 European Multigenerational Families With Moyamoya Angiopathy.

Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%.

Differential protein expression of blood platelet components associated with adverse transfusion reactions.

Platelets found within platelet components (PCs) intended for transfusion release inflammatory molecules. Despite the implementation of leukoreduction, some of these PCs are occasionally associated with adverse transfusion reactions (ATRs). The aim of this study was to decipher the platelet proteome in two types of PCs, buffy-coat-derived pooled PCs (PPCs) and single-donor apheresis PCs (SDA-PCs), associated with ATRs.

Molecular genetic diagnosis of Tunisian Glanzmann thrombasthenia patients reveals a common nonsense mutation in the ITGA2B gene that seems to be specific for the studied population.

: Glanzmann thrombasthenia is an inherited severe bleeding disease. Mutations associated with Glanzmann thrombasthenia are highly heterogeneous and occur across the two genes coding for the platelet αIIbβ3 integrin. This study was aimed at identifying Glanzmann thrombasthenia-associated novel mutations in Tunisian patients.

Soluble CD40L and CD62P levels differ in single-donor apheresis platelet concentrates and buffy coat-derived pooled platelet concentrates.

Background: Platelet storage lesions are structural and biochemical changes in platelet concentrates (PCs), and depend on variables in collection and processing, as well as secondary procedures and storage conditions; such lesions can be mitigated by the use of platelet additive solutions (PASs).

Study Design And Methods: This study investigated release of the inflammatory markers sCD40L and sCD62P by single-donor apheresis platelet concentrates (SDA-PCs) and buffy coat-derived pooled platelet concentrates (PPCs) before and after storage. SDA-PC and PPC samples (n = 9089) processed by various methods and stored for different durations were obtained following production in one regional setting, the French National Blood Service.

Assessment of soluble platelet CD40L and CD62P during the preparation process and the storage of apheresis platelet concentrates: Absence of factors related to donors and donations.

Platelet transfusions may be associated with certain adverse effects in recipients, potentially caused by the presence of biological response modifiers contained in the platelet concentrates. The aim of this study is to identify the parameters that reflect platelet activation during both the preparation process and the storage of platelet concentrates. A total of 3,949apheresis platelet concentrate samples were studied with regard to parameters related to the donor as well as to the preparation process and their storage.

The Non-Hemostatic Aspects of Transfused Platelets.

Platelets transfusion is a safe process, but during or after the process, the recipient may experience an adverse reaction and occasionally a serious adverse reaction (SAR). In this review, we focus on the inflammatory potential of platelet components (PCs) and their involvement in SARs. Recent evidence has highlighted a central role for platelets in the host inflammatory and immune responses.

Leucocyte cytokines dominate platelet cytokines overtime in non-leucoreduced platelet components.

Background: Leucoreduction of blood components, including platelet components, is strongly encouraged but not yet universal, especially outside high income countries. As both leucocytes and platelets secrete copious amounts of pro-inflammatory cytokines/chemokines under various conditions and during storage, we investigated the potential of the respective secretory programmes of these cells in order to evaluate their subsequent pathophysiological effects.

Material And Methods: A total of 158 individual non-leucoreduced platelet components were obtained from Tunisian donors and tested for characteristic biological response modifiers (BRM) of leukocytes (IL-1β, IL-8), platelets (sCD62P, sCD40L) and both cell types (TNF-α, RANTES) in the presence or absence of thrombin stimulation and after different periods of storage (up to 5 days).

Levels of human platelet-derived soluble CD40 ligand depend on haplotypes of CD40LG-CD40-ITGA2.

Increased circulating soluble CD40 ligand (sCD40L) is commonly associated with inflammatory disorders. We aimed to investigate whether gene polymorphisms in CD40LG, CD40 and ITGA2 are associated with a propensity to secrete sCD40L; thus, we examined this issue at the level of human platelets, the principal source of sCD40L. We performed single polymorphism and haplotype analyses to test for the effect of twelve polymorphisms across the CD40LG, CD40 and ITGA2 genes in blood donors.

Development of a highly resolutive method, using a double quadruplex tetra-primer-ARMS-PCR coupled with capillary electrophoresis to study CD40LG polymorphisms.

Polymorphisms in the CD40 ligand gene (CD40LG) are associated with various immunological disorders such as tumors, autoimmune and infectious diseases. The aim of this study was to develop a highly optimized double quadruplex tetra-primer amplification refractory mutation system PCR (double quadruplex T-ARMS-PCR) coupled with capillary electrophoresis to allow genotyping of eight relevant candidate CD40LG SNPs and to establish haplotypes. After conducting the double quadruplex T-ARMS-PCR, the genotypes obtained through agarose electrophoresis were compared with those obtained through capillary electrophoresis.