Patrick Short
A5078901635- Genomics and Rare Diseases
- Genomic variations and chromosomal abnormalities
- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- RNA Research and Splicing
- Cancer-related molecular mechanisms research
- MicroRNA in disease regulation
- Prenatal Screening and Diagnostics
- Phagocytosis and Immune Regulation
- Evolution and Genetic Dynamics
- Genetic factors in colorectal cancer
- Epigenetics and DNA Methylation
- RNA and protein synthesis mechanisms
- Chromosomal and Genetic Variations
- Genomics and Chromatin Dynamics
- Inflammasome and immune disorders
- Biotechnology and Related Fields
- RNA regulation and disease
- RNA Interference and Gene Delivery
- Healthcare Quality and Management
- Genetics and Neurodevelopmental Disorders
- Quality and Management Systems
- Chronic Kidney Disease and Diabetes
- Management and Organizational Studies
- Antenna Design and Optimization
Wellcome Sanger Institute
2017-2022
University of North Carolina at Chapel Hill
2012-2015
University of Oxford
2012
National Institute of Standards and Technology
1955
We estimated the genome-wide contribution of recessive coding variation in 6040 families from Deciphering Developmental Disorders study. The proportion cases attributable to variants was 3.6% patients European ancestry, compared with 50% explained by de novo mutations. It higher (31%) Pakistani owing elevated autozygosity. Half this burden is known genes. identified two genes not previously associated developmental disorders, KDM5B and EIF3F, functionally validated them mouse cellular...
Abstract Mutations in the germline generates all evolutionary genetic variation and is a cause of disease. Parental age primary determinant number new mutations an individual’s genome 1,2 . Here we analysed genome-wide sequences 21,879 families with rare diseases identified 12 individuals hypermutated between two seven times more de novo single-nucleotide variants than expected. In most (9 out 12), excess came from father. Two had drivers hypermutation, fathers carrying damaging DNA-repair...
Formulas, tables, and graphs are given for the probability distribution of instantaneous resultant amplitude sum a constant vector Rayleigh-distributed vector. It is emphasized that two distributions required to describe vector: its phase. A summary presented physical conditions which must be satisfied phenomenon exhibit statistical properties References made ways in these may used random variables occurring ionospheric, tropospheric, irregular terrain propagation problems. Finally,...
Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well more than 60,000 aggregated exomes the Exome Aggregation Consortium, investigate selection around splice sites quantify contribution of mutations DDs. Patterns purifying selection, a deficit variants in highly constrained genes healthy subjects, excess de novo patients...
Summary Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers human papillomavirus, rheumatic fever streptococcal infections 1, 2 . Similarly, infection by SARS-CoV-2 result in Long COVID, a condition characterized of fatigue pulmonary cognitive dysfunction 3–5 The biological mechanisms that contribute the development COVID remain be clarified. We leveraged COVID-19 Host Genetics Initiative 6, 7 perform genome-wide association...
Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process retrotransposition (RT). In humans several disorders have been attributed to RT, but role RT in severe developmental (DD) has not yet explored. Here we identify RT-derived events 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 likely causative patient's symptoms (0.04%), as well 2 gene retroduplications. Beyond identifying...
Summary De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated only account for minority the observed excess such DNMs. To identify novel genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, developed simulation-based statistical test to gene-specific enrichments We identified 285 significantly including 28 not previously robustly associated with DDs. Despite...
The health care industry in both the US and Canada has been under tremendous pressure to change reform during past decade. driven by escalating costs, increased demands from dissatisfied patients third-party payers. A movement that holds great promise for improved quality productivity is introduction of total management (TQM ). Spurred impressive results other industries, this compelling logical approach begun penetrate thinking accrediting agencies, business coalitions, private foundations...
How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark fidelity of stem cell differentiation programming, interpret pathogenicity noncoding variation. Here, we study histone modifications across thirteen tissues during organogenesis. We integrate data with transcription build an overview how differentially regulates alternative fates including by repression. Promoters from nearly 20,000...
Background Genomic variant prioritisation is one of the most significant bottlenecks to mainstream genomic testing in healthcare. Tools improve precision while ensuring high recall are critical successful clinical testing, particular for whole genome sequencing where millions variants must be considered each patient. Methods We developed EyeG2P, a publicly available database and web application using Ensembl Variant Effect Predictor. EyeG2P tailored efficient individuals with inherited...
Summary De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated only account for minority the observed excess such DNMs. To identify novel genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, developed simulation-based statistical test to gene-specific enrichments We identified 299 significantly including 49 not previously robustly associated with DDs. Despite...
Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to autosomal dominant due two different pathogenic APOA4 variants. A large family with chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing identification a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V ApoA4 protein. We identified other distantly related from our registry same chr11:116693454 C>T p.D33N. Both...
Summary Mutation in the germline is source of all evolutionary genetic variation and a cause disease. Previous studies have shown parental age to be primary determinant number new mutations seen an individual’s genome. Here we analysed genome-wide sequences 21,879 families with rare diseases identified 12 hypermutated individuals between two seven times more de novo single nucleotide variants (dnSNVs) than expected. In most these (8/12) excess could attributed father. We determined that had...
Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from Deciphering Developmental Disorders study, and, first time, estimated causal contribution recessive coding variation exome-wide. found that proportion cases attributable variants is surprisingly low in patients European...
Summary De novo mutations in hundreds of different genes collectively cause 25-42% severe developmental disorders (DD). The the remaining cases is largely unknown. role de regulatory elements affecting known DD associated or other essentially unexplored. We identified three classes putative almost 8,000 patients. Here we show that highly conserved fetal-brain active are significantly and specifically enriched neurodevelopmental disorders. a significant two-fold enrichment recurrently mutated...
Abstract Mobile genetic Elements (MEs) are segments of DNA which, through an RNA intermediate, can generate new copies themselves and other transcribed sequences the process retrotransposition (RT). In humans several disorders have been attributed to RT, but role RT in severe developmental (DD) has not yet explored. As such, we identified RT-derived events 9,738 exome sequenced trios with DD-affected probands as part Deciphering Developmental Disorders (DDD) study. We ascertained 9 de novo...
Abstract Mutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well >60,000 aggregated exomes the Exome Aggregation Consortium, investigate selection around splice site, quantify contribution of mutations DDs. Patterns purifying selection, a deficit variants in highly constrained genes healthy subjects excess de novo patients...