S. E. A. Leigh
A5062194841- Genetic factors in colorectal cancer
- Genomics and Rare Diseases
- Lipoproteins and Cardiovascular Health
- Cancer Genomics and Diagnostics
- Genomic variations and chromosomal abnormalities
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Genetic and Kidney Cyst Diseases
- Mitochondrial Function and Pathology
- RNA regulation and disease
- Cardiomyopathy and Myosin Studies
- Genetic Neurodegenerative Diseases
- Medical Malpractice and Liability Issues
- Genetic Associations and Epidemiology
- Cancer, Lipids, and Metabolism
- Genetic Syndromes and Imprinting
- DNA Repair Mechanisms
- Lipid metabolism and disorders
- Genomics and Phylogenetic Studies
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Ion Transport and Channel Regulation
Genomics England
2016-2025
Imperial College London
2022-2024
University Hospital Southampton NHS Foundation Trust
2024
Boston Children's Hospital
2024
Broad Institute
2024
NIHR Southampton Biomedical Research Centre
2024
University College London
1990-2023
Hospital for Sick Children
2022-2023
University of Toronto
2022-2023
SickKids Foundation
2022-2023
The U.K. 100,000 Genomes Project is in the process of investigating role genome sequencing patients with undiagnosed rare diseases after usual care and alignment this research health implementation National Health Service. Other parts project focus on cancer infection.
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...
Familial hypercholesterolemia (FH) (OMIM 143890) is most commonly caused by variations in the LDLR gene which encodes receptor for Low Density Lipoprotein (LDL) cholesterol particles. We have updated University College London (UCL) FH database (http://www.ucl.ac.uk/ldlr) adding variants reported literature since 2001, converting existing entries to standard nomenclature, and transferring Leiden Open Source Variation Database (LOVD) platform. As of July 2007 listed 1066 unique events. Sixty...
Summary Familial hypercholesterolemia (FH) is caused predominately by variants in the low‐density lipoprotein receptor gene ( LDLR ). We report here an update of UCL variant database to include reported literature and in‐house between 2008 2010, transfer LOVDv.2.0 platform https://grenada.lumc.nl/LOVD2/UCL‐Heart/home.php?select_db=LDLR ) pathogenicity analysis. The now contains over 1288 different FH patients: 55% exonic substitutions, 22% small rearrangements (<100 bp), 11% large...
Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine improved patient care. An essential requirement achieving standardized reliable interpretation data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) an exemplar the utility such resource: it has high incidence, favorable prognosis with early intervention treatment, cascade screening can be offered to...
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...
<h3>Background</h3> Familial hypercholesterolaemia (OMIM 143890) is most frequently caused by variations in the low-density lipoprotein receptor (<i>LDLR</i>) gene. Predicting whether novel variants are pathogenic may not be straightforward, especially for missense and synonymous variants. In 2013, Association of Clinical Genetic Scientists published guidelines classification variants, with categories 1 2 representing clearly or unlikely pathogenic, respectively, 3 unknown significance...
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...
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...
Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer
AimTo determine the frequency and spectrum of mutations causing Familial Hypercholesterolaemia (FH) in patients attending a single UK specialist hospital lipid clinic Oxford to identify characteristics contributing high mutation detection rate.Methods289 (272 probands) were screened sequentially over 2-year period for LDLR, APOB PCSK9 using standard molecular genetic techniques. The Simon Broome (SB) clinical diagnostic criteria used classify separate cohort 409 FH was replication.ResultsAn...
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,...
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...