A5072370875- Genomics and Rare Diseases
- Genetic and Kidney Cyst Diseases
- Cancer Genomics and Diagnostics
- Renal and related cancers
- Genetic factors in colorectal cancer
- Molecular Biology Techniques and Applications
- Genomic variations and chromosomal abnormalities
- BRCA gene mutations in cancer
- Trace Elements in Health
- Cancer, Hypoxia, and Metabolism
- Adrenal and Paraganglionic Tumors
- Genetic Syndromes and Imprinting
- Renal cell carcinoma treatment
- Iron Metabolism and Disorders
- Epigenetics and DNA Methylation
- Health, Environment, Cognitive Aging
- Pituitary Gland Disorders and Treatments
- DNA Repair Mechanisms
- Genetic Associations and Epidemiology
- Lung Cancer Treatments and Mutations
- Heavy Metal Exposure and Toxicity
- Colorectal Cancer Screening and Detection
- Glycogen Storage Diseases and Myoclonus
- CRISPR and Genetic Engineering
- Neurogenetic and Muscular Disorders Research
Sheffield Children's NHS Foundation Trust
2014-2025
University of Wisconsin–Madison
2022
Sheffield Teaching Hospitals NHS Foundation Trust
2016
University of Sheffield
2009-2013
Tel Aviv University
2013
The University of Melbourne
2013
Sheffield Children's Hospital
2007
University of Southampton
2006
Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B a significant number of clinically diagnosed cases. This has led concerns about genetic heterogeneity for this condition but also suggested presence unusual mutational mechanisms. We now present our findings 181 patients from United Kingdom with and biochemically confirmed disease. A total 116 different were detected, 32 which are novel. The overall mutation detection frequency was 98%. likelihood genes...
PurposeWhere multiple in silico tools are concordant, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework affords supporting evidence toward pathogenicity or benignity, equivalent to a likelihood ratio ~2. However, limited availability "clinical truth sets" prior use tool training limits their utility evaluation performance.MethodsWe created set 9,436 missense variants classified as deleterious tolerated clinically validated...
Our main objective was to identify baseline prognostic factors predictive of rapid disease progression in a large unselected clinical autosomal dominant polycystic kidney (ADPKD) cohort.
To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over 10-year period (2010-2020).All samples were tested by Sanger sequencing multiplex ligation-dependent probe amplification (MLPA) genes and/or next-generation panel 15 additional cystic including PKHD1 HNF1B. Two patients underwent exome or genome sequencing.Likely causative detected...
Advances in technology have led to a massive expansion the capacity for genomic analysis, with commensurate fall costs. The clinical indications testing evolved markedly; volume of sequencing has increased dramatically; and range professionals involved process broadened. There is general acceptance that our early dichotomous paradigms variants being pathogenic–high risk benign–no are overly simplistic. increasing recognition interpretation data requires significant expertise...
Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation risk and management patients. Consistency the weighting assigned to individual elements evidence has been much improved by American College Medical Genetics (ACMG) 2015 framework variant classification, UK Association Clinical Genomic Science (UK-ACGS) Best Practice Guidelines subsequent Cancer Variant Interpretation Group (CanVIG-UK) consensus specification CSGs. However, considerable...
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution inversions genetic disease unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare from the 100,000 Genomes Project. From a database hosting >500 million SVs, focused on 351 genes where haploinsufficiency confirmed mechanism and identified 47 ultra-rare rearrangements included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation...
Abstract Hereditary Breast and Ovarian Cancer (HBOC) is a genetic condition associated with increased risk of cancers. The past decade has brought about significant changes to hereditary breast ovarian cancer diagnostic testing new treatments, methods strategies, evolving information on associations. These best practice guidelines have been produced assist clinical laboratories in effectively addressing the complexities HBOC testing, while taking into account advancements since last were...
An 11-year-old presented with bilateral renal cell carcinoma (RCC) FH-deficient RCC confirmed by immunohistochemistry. WGS no coding variants but identified a rare intronic variant in FH (c.1391-269A>G). We illustrate how combined pathological and genomic investigations enabled precise diagnosis of the underlying cause an ultra-rare clinical presentation.
Advances in technology have made possible Multiplex Assays of Variant Effect (MAVEs), systematically generating functional data for many thousands genetic variants. Robust clinical validation and accessible online resources MAVE previously been identified as barriers to adoption new MAVEs. We delivered a survey during the November 2024 Cancer Interpretation Group (CanVIG-UK) meeting comprising NHS scientists geneticists, received 46 responses from individuals regularly performing variant...
Purpose Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH. This paper quantitatively weights the phenotypic context (PP4/PS4) of such very Methods We collated clinical diagnostic testing data on germline FH from 387 individuals with HLRCC 1,780 renal cancer, compared frequency 'very rare' each cohort against 562,295 population controls. generated pan-gene variant likelihood ratios...
Multiplex assays of variant effect (MAVEs) provide promising new sources functional evidence, potentially empowering improved classification germline genomic variants, particularly rare missense which are commonly assigned as VUS (variants uncertain significance). However, paradoxically, quantification clinically applicable evidence strengths for MAVEs requires construction truthsets comprising variants already robustly classified pathogenic and benign. In this study, we demonstrate how...
Wilson disease (WD) is an autosomal recessive of copper transport. The caused by a large number mutations in the ATP7B gene, some which appear to be population specific, whereas others are found probands from variety different ethnic backgrounds. This study presents results screening gene SSCP and sequencing order define spectrum seen British referrals for WD. 52 patients screened included 10 with non-British mixed ethnicity origin. identified 19 novel 18 that had been previously described....
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of renal failure. In patients who develop end-stage disease, transplantation replacement modality choice. For living related donation (LRKD), major challenge to exclude diagnosis ADPKD in potential donors. Renal imaging may not particularly younger donors and molecular testing advised. We report largest series date evaluating role for LRKD assessment.A cohort with were referred between April 2010 October...
SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma 30% wild-type gastrointestinal stromal tumours. Most PGV carriers present an apparently sporadic tumour, but often the variant has been inherited from parent who variant, not developed any clinical features. Studies suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when outside context a family history. Current recommended surveillance...
To describe national patterns of National Health Service (NHS) analysis mismatch repair (MMR) genes in England using individual-level data submitted to the Disease Registration (NDRS) by NHS regional molecular genetics laboratories.
Abstract Background Within the 2015 American College of Medical Genetics/Association Molecular Pathology (ACMG/AMP) variant classification framework, case-control observations can only be scored dichotomously as ‘strong’ evidence (PS4) towards pathogenicity or ‘nil’. Methods We developed PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative assignment based on observed frequencies in cases and controls. Binomial likelihoods are computed two models, each defined by pre-specified odds...