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Classification of Variants of Reduced Penetrance in High Penetrance Cancer Susceptibility Genes: Framework for Genetics Clinicians and Clinical Scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)
No full textPURPOSE: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network. METHODS: A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group (CStAG) working group. RESULTS: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants where (A) Active evidence suggests a reduced penetrance effect size (e.g. from case-control or segregation data) (B) Reduced penetrance effect is inferred from weaker/potentially-inconsistent observed data. CONCLUSIONS: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, whilst developed for CSGs, are potentially applicable to other clinical contexts.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults
No full textINTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD. METHODS AND ANALYSIS: ISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged =55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition. Eligible individuals are randomised in a 1:1 ratio to once-daily oral semaglutide or placebo, starting at 3 mg and up-titrating to 14 mg over 8 weeks. They will attend safety visits and provide blood samples to measure AD biomarkers at weeks 4, 8, 26 and 39. All cognitive assessments are repeated at week 26. The last study visit will be at week 52, when all baseline measurements will be repeated. The primary end point is the 1-year change in tau PET signal. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee (22/WM/0013). The results of the study will be disseminated through scientific presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN71283871.Published version, accepted version, submitted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia
No full textPURPOSE: PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. METHODS: Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. RESULTS: Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. CONCLUSION: By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
The Roles of GDF-9, BMP-15, BMP-4 and EMMPRIN in Folliculogenesis and In Vitro Fertilization
No full textGrowth differentiation factor 9 (GDF-9) contributes to early ovarian development and oocyte survival. Higher concentrations of GDF-9 in follicular fluid (FF) are associated with oocyte nuclear maturation and optimal embryo development. In in vitro fertilization (IVF), GDF-9 affects the ability of the oocyte to fertilize and subsequent embryonic development. Bone morphogenetic protein 15 (BMP-15) is involved in the regulation of ovarian function and affects oocyte development. During IVF, BMP-15 contributes to the formation of competent blastocysts. BMP-15 may play a role in embryo implantation by affecting endometrial receptivity. Bone morphogenetic protein 4 (BMP-4) is involved in the regulation of follicle growth and development and affects granulosa cell (GC) differentiation. In relation to IVF, BMP-4 is important for embryonic development, influences cell fate and differentiation, and plays a role in facilitating embryo-endometrial interactions during the implantation process. Extracellular matrix metalloproteinase inducer (EMMPRIN) is associated with ovulation and follicle rupture, promotes the release of mature eggs, and affects the modification of the extracellular matrix of the follicular environment. In IVF, EMMPRIN is involved in embryo implantation by modulating the adhesive properties of endometrial cells and promotes trophoblastic invasion, which is essential for pregnancy to occur. The purpose of the current article is to review the studies and recent findings of GDF-9, BMP-15, BMP-4 and EMMPRIN as fundamental factors in normal follicular development and in vitro fertilization.Published version, accepted version, submitted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Psychology Provision for People With Food Allergy: A Survey of UK Healthcare Professionals and Psychologists
No full textPublished version, accepted version (12 months embrago)RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Mycobacterium bovis infection of the appendix: a case of appendiceal tuberculosis in rural England
No full textAppendiceal tuberculosis is a rare mimic of acute appendicitis, demonstrated by several case reports of patients from tuberculosis endemic countries. On literature review, there are few cases reported of appendiceal tuberculosis in urban England, and no reports from rural England. This case describes a patient with primary appendiceal tuberculosis from a remote district hospital in England who underwent a diagnostic laparoscopy for suspected acute appendicitis. Intraoperatively, an abnormal appearance with extensive intra-abdominal adhesions was seen in addition to appendicitis, making the diagnosis dubious. Histology of the appendix was positive for acid-fast bacilli and culture of the intra-abdominal fluid revealed a diagnosis of Mycobacterium bovis infection. The mode of infection was thought to be reactivation of latent bovine tuberculosis from drinking unpasteurised milk in adolescence. Taking a focused history, particularly in those with a farming background, and intraoperative sampling for histology and culture are vital in the diagnosis of appendiceal tuberculosis.Published version, accepted version (12 month embargo), submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Defining tennis elbow characteristics - The assessment of magnetic resonance imaging defined tendon pathology in an asymptomatic population
No full textBACKGROUND: This radiological study aims to assess the prevalence of lateral elbow pathology in an asymptomatic population using 3.0T magnetic resonance imaging (MRI). METHODS: Bilateral elbow MRI was undertaken in 30 asymptomatic volunteers. Exclusion criteria included elbow pain within 3 months, elbow trauma or previous diagnosis of lateral epicondylar tendinopathy. Baseline patient-reported outcome measures were recorded along with age and body mass index (BMI). Two musculoskeletal radiologists independently graded the degree of abnormality at the common extensor tendon. RESULTS: Thirty volunteers were categorised according to age; 35-44 (n = 10), 45-54 (n = 11), and 55-65 (n = 9) with a 1:1 male-to-female ratio. Radiological evidence of tendon abnormality was found in 37% of volunteers. The proportion with abnormal findings increased with age; 35-44 (10%), 45-54 (36%), 55-65 (67%) and BMI; 18-24.9 (23%), 25-29.9 (43%), > 30 (67%). Changes were generally 'mild' or 'moderate', with a single volunteer showing 'severe' pathology. Kappa for the radiographic agreement was 0.91 (0.83-0.98). DISCUSSION: This study has demonstrated MRI findings suggestive of pathology at the common extensor tendon to be prevalent in an asymptomatic population, increasing with age and BMI. This draws into question the diagnostic and prognostic value of MRI imaging in lateral epicondylar tendinopathy, especially in older patients.Published version, accepted version (12 month embargo), submitted versionFull Text unavailable for 1 year from time of publication
Complications of fibrotic interstitial lung disease for the general radiologist
No full textInterstitial lung diseases (ILDs) are a heterogeneous group of conditions characterised by non-infective inflammation and scarring of the lung parenchyma. They are not infrequently encountered by the general radiologist in both acute and outpatient reporting settings who may even be the first to make the diagnosis. In the acute setting, patients with ILD can present with respiratory deterioration due to a number of causes and in addition to the common causes of dyspnoea, an acute exacerbation of ILD needs to be considered. An exacerbation can be initiated by common triggers such as infection, pulmonary embolism (PE), and heart failure, and it can also be initiated by an insult to the lung or occur due to an unknown cause. Particular care needs to be taken when interpreting computed tomography (CT) examinations in these patients as the findings of an acute exacerbation are non-specific and patient and technical factors can cause spurious appearances including dependent changes, breathing artefact and contrast medium opacification. In the non-acute setting, patients with ILD are at increased risk of lung cancer and pulmonary hypertension (PH), with lung cancer being a particularly important consideration as treatments carry the risk of triggering an acute exacerbation or deterioration in lung function. Overall, this review aims to provide an overview for the general radiologist of additional factors to consider when interpreting scans in patients with ILD and how the presence of ILD impacts the differential diagnoses and complications that can occur in these patients in both acute and non-acute settings.Published version, accepted version (12 month embargo)Supports Open Acces
Saturation genome editing of BAP1 functionally classifies somatic and germline variants
No full textMany variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.Accepted version (6 months embargo), submitted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations
No full textAutosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2-19% across genetically inferred ancestry groups and was significantly correlated with average autozygosity. Established autosomal recessive developmental disorder-associated (ARDD) genes explained 84.0% of the total autosomal recessive coding burden, and 34.4% of the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. Statistical analyses identified two novel ARDD genes: KBTBD2 and ZDHHC16. This study expands our understanding of the genetic architecture of developmental disorders across diverse genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes.This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text