A5063495458- Cancer Genomics and Diagnostics
- Genomics and Rare Diseases
- Epigenetics and DNA Methylation
- Genetic factors in colorectal cancer
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- Lymphoma Diagnosis and Treatment
- Genomic variations and chromosomal abnormalities
- RNA and protein synthesis mechanisms
- Genetic and Kidney Cyst Diseases
- RNA regulation and disease
- Genetics and Neurodevelopmental Disorders
- Chronic Lymphocytic Leukemia Research
- Cancer-related gene regulation
- Cardiomyopathy and Myosin Studies
- Metabolism and Genetic Disorders
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Cancer-related molecular mechanisms research
- Cell Adhesion Molecules Research
- Ion channel regulation and function
- Ion Transport and Channel Regulation
- Platelet Disorders and Treatments
Genomics England
2020-2024
University of Surrey
2024
Queen Mary University of London
2016-2023
Children’s Institute
2023
University College London
2023
University of Pavia
2023
University of Manchester
2023
European Molecular Biology Laboratory
2023
University of Helsinki
2023
National Institutes of Health
2023
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. contrasted our results to two independent datasets, International Cancer Genome Consortium (ICGC) Hartwig Foundation, involving 18,640 cancers total. Our add 40...
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing data from nearly 10 000 individuals recruited within the Genomics England project to investigate normal pathogenic variation of RFC1 repeat. We identified three novel motifs, AGGGC (n = 6 five families), AAGGC 2 one family) AGAGG 1), associated with CANVAS...
We are indebted to the patients for donating tumor specimens as part of this study. The authors thank Centre de Ressources Biologiques (CRB)-Sante Rennes (BB-0033-00056) for patient samples, Queen Mary University London Genome Centre for Illumina Miseq sequencing, and support by National Institute Health Research (NIHR) Biomedical at Guy’s St Thomas’ NHS Foundation Trust King’s College London Hiseq sequencing. views expressed are those not necessarily those NHS, NIHR, or Department...
Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down maternal line, most recently in three families where several individuals harbored a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report similar genetic signature 7 11,035 trios, allelic fractions 5-25%, implying inheritance mtDNA 0.06% offspring. However, analysing nuclear whole genome sequence, observe likely large rare or unique...
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures how essential gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice the International Mouse Phenotyping Consortium essentiality carried out human cell lines. We propose cross-species classification across Full Spectrum Intolerance Loss-of-function (FUSIL)...
The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but preferentially protected transcription-coupled repair
Abstract The value of genome-wide over targeted driver analyses for predicting clinical outcomes cancer patients is debated. Here, we report the whole-genome sequencing 485 chronic lymphocytic leukemia enrolled in trials as part United Kingdom’s 100,000 Genomes Project. We identify an extended catalog recurrent coding and noncoding genetic mutations that represents a source future studies provide most complete high-resolution map structural variants, copy number changes global genome...
Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity incompletely explained differences in the causal variant or clinical factors. In 34 adults with SCN1A-related syndrome, we show additional genomic variation beyond contributes to phenotype and diversity, excess of variants epilepsy-related genes as set examples blended phenotypes,...
Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer
The development of computational methods to assess pathogenicity pre-messenger RNA splicing variants is critical for diagnosis human disease. We assessed the capability eight algorithms, and a consensus approach, prioritize 249 uncertain significance (VUSs) that underwent functional analyses. algorithms differentiate VUSs away from immediate splice site as being 'pathogenic' or 'benign' likely have substantial impact on diagnostic testing. show SpliceAI best single strategy in this regard,...
Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis PCD has management implications including addressing comorbidities, implementing fertility counselling future access to PCD-specific treatments. Diagnostic testing be complex; however, moving rapidly research into clinical diagnostics would confirm bronchiectasis.This...
Abstract Background Whole-genome sequencing (WGS) of cancers is becoming an accepted component oncological care, and NHS England currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share experience East Genomic Medicine Centre (East-GMC), reporting feasibility clinical utility centralised individual locally. Methods Non-consecutive solid tumours were recruited into pilot 100 K project at our Centre. Variant...
Alport syndrome is the commonest inherited kidney disease and nearly half pathogenic variants in COL4A3-COL4A5 genes that cause result Gly substitutions. This study examined molecular characteristics of substitutions determine severity clinical features. Pathogenic COL4A5 affecting Leiden Open Variation Database males with X-linked were correlated age at failure (n = 157) hearing loss diagnosis 80). Heterozygous COL4A3 COL4A4 304) autosomal dominant risk haematuria UK 100,000 Genomes...
The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact strongly associate with function and risk of chronic (CKD) general population. It is unknown whether intermediate-effect contribute to CKD. Here, candidate were identified using large-population ADTKD cohorts. Biological phenotypical effects investigated cell models,...
CAG repeat expansions in exon 1 of the AR gene on X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with variety extra-neurological symptoms. The disease has reported male prevalence approximately 1:30 000 or less, but expansion frequency is unknown. We established pipeline, which combines use ExpansionHunter tool visual validation, to detect whole-genome sequencing data, benchmarked it fragment PCR sizing, applied 74 277...
PurposeDetermining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD).MethodsGenome and exome sequencing were performed for five unrelated cases IRD with no identified variant. In vitro assays developed to validate (fibroblast assay, induced pluripotent stem cell [iPSC] derived organoids, a dynein motility assay).ResultsFour novel (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) one previously reported variant (V5,...
Lamins are the major component of nuclear lamina, maintaining structural integrity nucleus. Lamin A/C variants well established to cause a spectrum disorders ranging from myopathies progeria, termed laminopathies. Phenotypes resulting in LMNB1 and LMNB2 have been much less clearly defined.
Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution variants in non-coding DNA elements that result cryptic splicing and regulate expression has not been explored. We analyzed whole-genome sequencing (WGS) data discovery cohort 209 pediatric CMP patients 1953 independent replication genomes exomes. searched for protein-coding variants, predicted to affect the function or genes. Thirty-nine percent harbored...
Abstract Background Cancer genome sequencing enables accurate classification of tumours and tumour subtypes. However, prediction performance is still limited using exome-only for types with low somatic mutation burden such as many paediatric tumours. Moreover, the ability to leverage deep representation learning in discovery entities remains unknown. Methods We introduce here Mutation-Attention (MuAt), a neural network learn representations simple complex alterations In contrast previous...