Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia.

Background: Primary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia. Most cases are inherited recessively, due to variants in >50 genes that result in abnormal or absent motile cilia. This leads to chronic upper and lower airway disease, subfertility, and laterality defects.

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies as a candidate in PLS.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease.

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies as a candidate in PLS.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease.

Redefining precision radiotherapy through liquid biopsy.

Precision radiotherapy refers to the ability to deliver radiation doses with sub-millimetre accuracy. It does not however consider individual variation in tumour or normal tissue response, failing to maximise tumour control and minimise toxicity. Combining precise delivery with personalised dosing, through analysis of cell-free DNA, would redefine precision in radiotherapy.

Students' and staffs' views and experiences of asymptomatic testing on a university campus during the COVID-19 pandemic in Scotland: a mixed methods study.

Objectives: To explore the acceptability of regular asymptomatic testing for SARS-CoV-2 on a university campus using saliva sampling for PCR analysis and the barriers and facilitators to participation.

Design: Cross-sectional surveys and qualitative semistructured interviews.

Setting: Edinburgh, Scotland.

Genotype-phenotype characterisation of long survivors with motor neuron disease in Scotland.

Background: We investigated the phenotypes and genotypes of a cohort of 'long-surviving' individuals with motor neuron disease (MND) to identify potential targets for prognostication.

Methods: Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as > 8 years from diagnosis.

The role of liquid biopsy in management of the neck with indeterminate response on post-treatment imaging following non-surgical management of oropharyngeal cancer.

Introduction: This study aimed to determine if post-treatment HPV cell-free DNA (cfDNA) can assist in the decision-making process for salvage neck dissection in patients following non-surgical treatment of oropharyngeal squamous cell carcinoma (OPSCC) with a partial response in the neck on imaging at 12 weeks post-treatment.

Methods: 86 patients who completed treatment were prospectively recruited through the regional multidisciplinary team (MDT). Treatment response was categorised as complete response (CR), partial response (PR) or progressive disease on 12-week post-treatment imaging.

Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways.

P2RX7, an ionotropic receptor for extracellular adenosine triphosphate (ATP), is expressed on immune cells, including macrophages, monocytes, and dendritic cells and is upregulated on nonimmune cells following injury. P2RX7 plays a role in many biological processes, including production of proinflammatory cytokines such as interleukin (IL)-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity.

Ancient DNA at the edge of the world: Continental immigration and the persistence of Neolithic male lineages in Bronze Age Orkney.

Orkney was a major cultural center during the Neolithic, 3800 to 2500 BC. Farming flourished, permanent stone settlements and chambered tombs were constructed, and long-range contacts were sustained. From ∼3200 BC, the number, density, and extravagance of settlements increased, and new ceremonial monuments and ceramic styles, possibly originating in Orkney, spread across Britain and Ireland.

Inherited Thoracic Aortic Disease: New Insights and Translational Targets.

Inherited thoracic aortopathies denote a group of congenital conditions that predispose to disease of the thoracic aorta. Aortic wall weakness and abnormal aortic hemodynamic profiles predispose these patients to dilatation of the thoracic aorta, which is generally silent but can precipitate aortic dissection or rupture with devastating and often fatal consequences. Current strategies to assess the future risk of aortic dissection or rupture are based primarily on monitoring aortic diameter.

Impulsivity is a heritable trait in rodents and associated with a novel quantitative trait locus on chromosome 1.

Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders. Although a number of genes for impulsivity have been identified, no study to date has carried out an unbiased, genome-wide approach to identify genetic markers associated with impulsivity in experimental animals. Herein we report a linkage study of a six-generational pedigree of adult rats phenotyped for one dimension of impulsivity, namely premature responding on the five-choice serial reaction time task, combined with genome wide sequencing and transcriptome analysis to identify candidate genes associated with the expression of the impulsivity trait.

Absolute measurement of the tissue origins of cell-free DNA in the healthy state and following paracetamol overdose.

Background: Despite the emergence of cell-free DNA (cfDNA) as a clinical biomarker in cancer, the tissue origins of cfDNA in healthy individuals have to date been inferred only by indirect and relative measurement methods, such as tissue-specific methylation and nucleosomal profiling.

Methods: We performed the first direct, absolute measurement of the tissue origins of cfDNA, using tissue-specific knockout mouse strains, in both healthy mice and following paracetamol (APAP) overdose. We then investigated the utility of total cfDNA and the percentage of liver-specific cfDNA as clinical biomarkers in patients presenting with APAP overdose.

Spatial transcriptomics identifies spatially dysregulated expression of GRM3 and USP47 in amyotrophic lateral sclerosis.

Aims: The mechanisms underlying the selective degeneration of motor neurones in amyotrophic lateral sclerosis (ALS) are poorly understood. The aim of this study was to implement spatially resolved RNA sequencing in human post mortem cortical tissue from an ALS patient harbouring the C9orf72 hexanucleotide repeat expansion to identify dysregulated transcripts that may account for differential vulnerabilities of distinct (i) cell types and (ii) brain regions in the pathogenesis of ALS.

Methods: Using spatial transcriptomics (ST) we analysed the transcriptome of post mortem brain tissue, with spatial resolution down to 100 μm.

Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions.

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population.

An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort.

The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.

Camk2n1 Is a Negative Regulator of Blood Pressure, Left Ventricular Mass, Insulin Sensitivity, and Promotes Adiposity.

Metabolic syndrome is a cause of coronary artery disease and type 2 diabetes mellitus. Camk2n1 resides in genomic loci for blood pressure, left ventricle mass, and type 2 diabetes mellitus, and in the spontaneously hypertensive rat model of metabolic syndrome, Camk2n1 expression is cis-regulated in left ventricle and fat and positively correlates with adiposity. Therefore, we knocked out Camk2n1 in spontaneously hypertensive rat to investigate its role in metabolic syndrome.

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C.

A Dominantly Inherited 5' UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer.

Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5' UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer.