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Research at UCL into the genetics of neuronal ceroid lipofuscinoses (NCL) — also known as Batten Disease - has had a global impact on the diagnosis and understanding of this group of diseases. The identification of genes and mutations has led to new diagnostic tests, which inform clinical management in terms of expected disease course and choice of the most effective drugs; prenatal and pre-implantation diagnoses for prevention are also possible. The group has established a new classification of diseases according to gene-based nomenclature. Information about all genes that underlie NCL has been collated in the NCL Mutation Database, which is freely available on the NCL Resource website. The group has also engaged closely with professionals and affected families to maximise the reach and understanding of research.
Research by Professor David Brook on inherited disorders has made a major contribution to the human genetics field. The work involved gene identification and mutation detection for genotype/phenotype correlation analysis in patients, which has led to the development of diagnostic tests for inherited conditions including myotonic dystrophy type 1 (DM1), Holt-Oram Syndrome (HOS), and campomelic dysplasia (CD). The tests have benefitted patients in the UK and throughout the rest of the world and in many cases they have been used as the definitive diagnostic measure. The assays developed have also been used in affected families for prenatal diagnosis to enable informed reproductive decisions.
Research at the UCL School of Pharmacy has positively influenced healthcare in startle disease/hyperekplexia, a rare disease that affects humans and several animal species, including dogs, horses and cattle. The identification and functional characterisation of mutations in genes involved in human startle disease by researchers at the School has improved genetic diagnostics and patient care. Our research on startle disease in cattle and dogs has also led to new non- invasive diagnostic tests that have alleviated animal suffering and reduced negative economic impacts on farmers. Overall, our findings have been translated into tangible benefits for the human and animal populations affected by this disease and have changed the way in which the disease is diagnosed and treated. We have also significantly increased the awareness of this rare disorder by communicating with academics, healthcare and veterinary professionals, and the general public.
The Caldecott/Jeggo/O'Driscoll laboratories have identified human genetic diseases that are caused by defects in genes involved in DNA strand-break repair. Many of these diseases are associated with neurological pathologies such as cerebellar ataxia (resulting in poor balance, movement control, and patients often being wheelchair bound), microcephaly (smaller-than-normal head circumference), and developmental delay. The Caldecott/Jeggo/O'Driscoll laboratories have engaged in identifying/diagnosing patients with such diseases as a service to clinicians/clinical geneticists in the UK National Health Service (NHS) and worldwide. Since 2008, these laboratories have identified the underlying genetic defect in more than 150 patients with a range of hereditary DNA damage-related disorders. In particular, these laboratories have diagnosed patients with genetic defects in the DNA damage response genes Lig4, NHEJ1-XLF, DCLRE1C-Artemis, PRKDC-DNA-PKcs, PCNT, ORC1, ATRIP, ATR, and TDP2. These diagnoses benefit both the clinical geneticist and the patient; identifying not only the cause of the patient's disease but also enabling better disease management. For example, if not first diagnosed, standard chemotherapeutic regimes can be fatal in cancer patients who harbour homozygous TDP2 mutations, and standard conditioning regimes used during bone-marrow transplantation can be fatal in LIG4 Syndrome patients. These diagnoses can therefore translate into increased patient survival.
Impact: Health and welfare; policy and guidelines; public engagement. The identification of >20 genes linked to human developmental and childhood degenerative disorders.
Significance: Definitive diagnosis is essential for genetic counselling, prenatal screening and postnatal management.
Beneficiaries: People with developmental disorders and their families, prospective parents, the NHS and healthcare delivery organisations; public understanding of genetic disorders.
Attribution: Researchers from UoE identified/characterised all the genes described, and their mutation in disease.
Reach: Worldwide: these developmental disorders affect thousands of people. Genetic tests established as a result of the research are provided for people from 35 countries on all continents.
Diagnostic tests have been successfully developed for identification of the cause of erythrocytosis, particularly in patients with unexplained forms of this rare disease. A diagnostic service with worldwide reach was developed for the genetic characterisation of patients that carry mutations identified by the Queens's group. It deals with approximately 100 samples per year referred for investigation for this rare disease from the UK, Europe and further afield. Proper diagnosis helps in management of patients with erythrocytosis where the problem is not mutation in one of the familiar causative genes. A pan-European web-based database has been established to collect information on long-term outcomes to inform patient management.
Development of the human cell GADD45a assay enabled accurate identification of carcinogens in vitro, with a low rate of misleading positives. Through the spin-out company Gentronix, this research is reducing costs to industry and decreasing the use of animals in research. Industrial collaboration has enabled commercial adoption of the technology in many sectors. With a 10-fold increase in orders in 2012 versus 2008, Gentronix is a profitable business employing 17 people and with an annual turnover of £1.88m. During 2008-12, Gentronix released a series of new products, established testing services, and signed a product license agreement with GlaxoSmithKline. More than 100 companies worldwide are using Gentronix kits, including pharmaceutical, agricultural and health and beauty companies, along with manufacturers of food flavourings and household goods. The Gentronix assay is currently being reviewed by the European Centre for the Validation of Alternative Methods.
Research at the Centre for Cutaneous Research at Queen Mary has led to gene discovery and molecular diagnosis for a number of single gene skin disorders and associated syndromes including hearing loss, inflammatory bowel disease, cardiomyopathy and oesophageal cancer. It has identified GJB2 mutations (encoding Cx26) as major cause of genetic hearing loss (20-50% of all cases) and ABCA12 mutations with the (often fatal) recessive skin condition Harlequin Ichthyosis. Impacts include: 1) increased medical and scientific awareness/knowledge of the inherited basis of these conditions, 2) changes in clinical practice and molecular diagnosis, 3) improved information for patients, parents and the public.
Research on clinically important red blood cell membrane proteins has helped avoid unnecessary treatment of Rhesus negative pregnant women and enabled the early diagnosis of a rare kidney disease. During the late 1990s, researchers at the University of Bristol, in collaboration with the Blood Service in Bristol, cloned, sequenced and characterised many red blood cell membrane proteins important for transfusion, including the Rhesus proteins and Band 3/AE1 (SLC4AE1 gene). The work on Rhesus proteins facilitated the use of less invasive genetic screening methods to ascertain whether treatment was required to avoid Haemolytic Disease of the Foetus or Newborn (HDFN). In the UK, 5,000 women have been screened since 2001. Within the first six months of implementation of a Danish national screening program in January 2010, 862 women avoided unnecessary treatment. Reducing unnecessary treatment of mothers has saved resources and avoided unnecessary exposure to human derived blood products. In addition, research that has identified specific SLC4AE1 gene mutations that cause the rare kidney disease called distal renal tubular acidosis has enabled the early diagnosis and treatment of the disease, resulting in improved outcomes for patients.
Impact on society (non-profit organisations) and public attitudes: The discovery of the reversibility of Rett syndrome in a mouse model for the disease has changed attitudes and awareness amongst families of sufferers and has led directly to the formation of two new charities: the Rett Syndrome Research Trust (US) and ReverseRett (UK).
Impact on health and welfare: Two new clinical interventions are being trialled with Rett syndrome patients.
Beneficiaries: Families living with Rett syndrome worldwide.
Significance and Reach: The research has given hope to thousands of families world-wide and has prompted an active philanthropic drive to fund research into a cure based on the UoE findings. The RSRT has raised $15 million since 2008. The incidence of Rett syndrome is 1 in 10,000 females. Some 16,000 individuals have Rett syndrome in the USA, and an estimated 2,400 in the UK.
Attribution: The research was carried out at UoE led by Adrian Bird. The critical underpinning paper was the UoE demonstration of reversibility (2007).