A5064670089- Pancreatic function and diabetes
- Genomics and Rare Diseases
- Genetics and Neurodevelopmental Disorders
- Cytomegalovirus and herpesvirus research
- Diabetes and associated disorders
- Metabolism, Diabetes, and Cancer
- RNA modifications and cancer
- Congenital heart defects research
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Genetic Neurodegenerative Diseases
- Genomic variations and chromosomal abnormalities
- Immune Cell Function and Interaction
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Polyamine Metabolism and Applications
- Connective tissue disorders research
- RNA regulation and disease
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Mitochondrial Function and Pathology
- Bacterial Genetics and Biotechnology
- Enzyme Production and Characterization
- Prenatal Screening and Diagnostics
- Herpesvirus Infections and Treatments
- Hereditary Neurological Disorders
Royal Devon & Exeter NHS Foundation Trust
2019-2025
University of Exeter
2015-2024
Genomics (United Kingdom)
2020-2022
Cardiff University
2000-2019
University College London
2019
Government Medical College
2019
Banaras Hindu University
2019
Institute of Medical Sciences
2019
The Royal Free Hospital
2019
Columbia University Irving Medical Center
2019
Current genetic tests for diagnosing monogenic diabetes rely on selection of the appropriate gene analysis according to patient’s phenotype. Next-generation sequencing enables simultaneous multiple genes in a single test. Our aim was develop targeted next-generation assay detect mutations all known MODY and neonatal genes. We selected 29 which have been reported cause diabetes, MODY, maternally inherited deafness (MIDD) or familial partial lipodystrophy (FPLD). An exon-capture designed...
We have asked how the human cytomegalovirus major immediate-early 1 (IE1) and 2 (IE2) proteins act to transactivate heterologous cellular viral promoters. Here we show that transactivation of immunodeficiency virus long terminal repeat 70,000-molecular-weight heat shock protein (hsp70) promoter by IE1 is TATA box independent does not interact directly with box-binding factor TFIID. Conversely, these promoters IE2 dependent a direct interaction between TFIID occurs, suggesting mediated through
Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be causative gene, and c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested play a role pathogenesis of acromegaly. We studied 153 patients (58 females 95 males) with gigantism. mutation-negative cases were screened for duplication through copy number variation...
Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis five informative identified a single significant locus on chromosome 16p13.2 (logarithm odds score 6.5). Sequencing the coding regions all linked genes failed to identify biallelic mutations. Instead, we...
Significance We report a disease-causing mutation in the β-cell–enriched MAFA transcription factor. Strikingly, missense p.Ser64Phe was associated with either of two distinct phenotypes, multiple insulin-producing neuroendocrine tumors pancreas—a condition known as insulinomatosis—or diabetes mellitus, recapitulating physiological properties both an oncogene and key islet β-cell The implication these human phenotypes will provide insights into how this factor regulates activity well...
Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal have been identified to date. There are still patients who novel genetic syndromes. We performed exome sequencing in patient and his unrelated, unaffected parents identify the etiology characterized by diabetes, sensorineural deafness, congenital cataracts. Further testing was 311 diagnosed before 1 year age whom all known causes had excluded. 5 patients, including...
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,...
The 86K immediate early (IE) 2 protein of human cytomegalovirus trans-activates a number homologous and heterologous promoters, including the cellular promoter for 70K heat-shock (hsp 70), immunodeficiency virus long terminal repeat. We have previously shown that IE2 these two promoters in TATA-dependent manner, is able to form direct contact with TATA-box binding (TBP) vitro. now show binds basic repeat region TBP. In addition can second general transcription factor, TFIIB. mapped TBP-...
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of mutations in a large cohort with permanent neonatal diabetes (PNDM).The 11 coding exons polyadenylation region were sequenced 26 male subjects diagnosed before 6 months age whom common genetic causes PNDM had been excluded. Ten at least one additional immune-related disorder, remaining 16 isolated diabetes.We...
<h3>Background</h3> Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a heterozygous mutation HNF4A. Heterozygous HNF4A mutations cause beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic (a renal proximal tubulopathy) is described but no genetic has been defined. <h3>Methods Results</h3> report six patients for the p.R76W who have nephrocalcinosis addition to...
Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome coding regions and conserved splice sites has been very successful in identification disease-causing mutations, targeting these extended clinical diagnostic testing from fewer than ten genes per phenotype to more 100. Noncoding mutations have less extensively studied despite evidence mRNA for existence deep intronic >20 genes. We investigated individuals with...
Abstract The long-read sequencers from Pacific Bioscience (PacBio) and Oxford Nanopore Technologies (ONT) offer the opportunity to phase mutations multiple kilobases apart directly sequencing reads. In this study, we used long-range PCR with ONT PacBio two variants 9 kb in RET gene. We also re-analysed data a recent paper which had apparently successfully clinically important haplotypes at CYP2D6 HLA loci. From these analyses, demonstrate PCR-chimera formation during amplification reference...
Congenital hyperinsulinaemic hypoglycaemia (HH) can occur in isolation or it may present as part of a wider syndrome. For approximately 40%-50% individuals with this condition, sequence analysis the known HH genes identifies causative mutation. Identifying underlying genetic aetiology remaining cases is important diagnosis will inform on recurrence risk, guide medical management and provide valuable insights into β-cell physiology. We sequenced exome child persistent diazoxide-responsive HH,...
Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential test for future pregnancies. We describe our novel strategy exome sequencing parental DNA samples to diagnose recessive monogenic an audit first 50 referred.Exome was carried out consecutive series who had 1 more pregnancies affected with lethal prenatal-onset disorder. In all cases, there insufficient...
To report the retinal phenotype and associated genetic systemic findings in patients with mitochondrial disease. Retrospective case series. Twenty-three retinopathy disease, including chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes deafness (MIDD), encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS), Kearns-Sayre syndrome, neuropathy, ataxia, retinitis pigmentosa (NARP) other manifestations. Review of notes, imaging, electrophysiologic...
Identifying genes linked to extreme phenotypes in humans has the potential highlight biological processes not shared with all other mammals. Here, we report identification of homozygous loss-of-function variants primate-specific gene ZNF808 as a cause pancreatic agenesis. is member KRAB zinc finger protein family, large and rapidly evolving group epigenetic silencers which target transposable elements. We show that loss vitro results aberrant activation regulatory contained elements it...
Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There often limited fetal DNA available for investigation. We investigated a strategy diagnosing autosomal recessive lethal non-consanguineous pedigrees with multiple fetuses. Exome sequencing was performed to identify genes where each parent heterozygous rare...
Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) a female preponderance.A 4-year-old boy presented rapid growth over previous 2 years. He complained of headaches and had coarse facial features. His height Z-score was +4.89, weight +5.57. Laboratory testing revealed elevated serum prolactin (185 μg/L; normal, <18 μg/L), IGF-1 (745 64-369 fasting GH > 35.0 μg/L....
We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in syndrome of pancreatic agenesis and abnormal forebrain development three individuals similar phenotype mice. is transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells pluripotent state. These findings suggest plays role neurological describe novel genetic holoprosencephaly. Discovering genes with mutations causal crucial to...