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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.
Research from the University of Oxford's Clinical Genetics Laboratory initiated the introduction of an upper age limit of 40 years for sperm donors in the UK and internationally and led to increased public awareness of the effect of paternal age in the transmission of inherited disease. Oxford researchers, led by Professor Andrew Wilkie, were the first to describe the exclusively paternal transmission of de novo mutations, in a rare craniofacial disorder called Apert Syndrome; they also showed that the accumulation of such mutations leads to a disproportionate risk of disease transmission with age. By showing that the frequency of mutations increases with paternal age, this research contributed to important changes in clinical practice relating to sperm donation. This has also had a significant cultural impact, as the research and its clinical outcomes have challenged public perceptions of paternal age.
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.
Individuals with Xeroderma pigmentosum (XP) are extremely susceptible to sunlight-induced skin cancers and, in some cases, develop neurological problems. Alan Lehmann has developed a cellular diagnostic test for this disorder. This test is now conducted as an integral part of a multi-disciplinary XP specialist clinic in London, which was established as a direct result of Alan Lehmann's research in Sussex and which has led to the improved diagnosis and management of the disorder and an improved quality of life for affected individuals.
Research at UCL on human haemolytic anaemias known as the `hereditary stomatocytoses' has improved diagnosis of these conditions, meaning that patients now avoid unnecessary and potentially life-threatening splenectomies, and inappropriate investigation and treatment for raised potassium levels. Identification of a common single nucleotide polymorphism that causes apparently normal red blood cells to leak salt when cooled (as is normal procedure with donated blood) has raised awareness of this issue in the NHS Blood and Transfusion service, with the result that individuals with this condition have been identified among existing donors, and work is underway to develop a screening method to exclude such individuals from donating blood that cannot be stored safely. Finally, the research has facilitated diagnosis of the recessive metabolic disorder phytosterolaemia by blood count, allowing these individuals to be given appropriate dietary treatment to control their cholesterol levels.
The myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies. Research led by Professor Green at Cambridge University reported that many MPN patients carry a JAK2V617F mutation and identified JAK2 exon 12 mutations associated with an MPN variant often previously diagnosed as idiopathic erythrocytosis. These outcomes led to tests for JAK2 mutations being established in the Eastern Region Haemato-oncology Diagnostic Service (Addenbrooke's hospital), providing a paradigm for other UK molecular diagnostic services. Tests for JAK2V617F and exon 12 mutations have greatly simplified, and improved the accuracy of, the diagnosis of MPN patients world-wide, and are now firmly embedded as front-line tests in national and international guidelines.
Research by Professor Elizabeth Shephard at the UCL Research Department of Structural and Molecular Biology has led to identification of the genetic origin of Trimethylaminuria (TMAU), commonly known as fish-odour syndrome. This has led to genetic diagnosis and genetic counselling for TMAU in the UK, Europe, USA and Canada, and the publication of guidelines for treatment and diagnosis. Shephard has engaged closely with patient groups over the years to publicise her findings. There is now an increased understanding among medical practitioners and the public that the body odour produced is due to a metabolic defect of genetic origin, and is not due to poor hygiene.
Ataxia telangiectasia (A-T) is an inherited disease affecting multiple systems in the body, causing severe disability and death. Work led by Professor Malcolm Taylor at the University of Birmingham has been central to the biological and clinical understanding of this disease, from the identification of the gene responsible to the clarification of related conditions with different underlying causes. As a result of this work, within the 2008-13 period, his laboratory has been designated the national laboratory for clinical diagnosis of A-T — a service also offered internationally — and has also changed national screening policy for breast cancer, following his confirmation of the increased risks of A-T patients and those who carry a single copy of the gene for this type of tumour. Furthermore, he has contributed in a major way to patient support for this condition.
Basic molecular genetic research undertaken over the last 20 years by UCL Cardiovascular Genetics has had a significant impact on the identification and treatment of patients with familial hypercholesterolaemia (FH). We have developed DNA testing methods in the three genes currently known to cause FH and have established DNA diagnostic protocols which are now in wide use throughout the UK. As a direct consequence of our work, we estimate that up to 3,000 FH patients in the UK have had their diagnosis of FH confirmed by a DNA test. Our work led to the National Institute of Health and Clinical Excellence (NICE) in 2008 strongly recommending DNA and cascade testing and early treatment with high intensity statins, and furthermore, the inclusion of FH checks in the NHS's Vascular Checks programme.
Our research has had impact on the activities of practitioners and their services, health and welfare of patients, on society and on public policy. New diagnostic tests for genetic deafness have been introduced, and healthcare guidelines and professional standards adopted through our investigation of the aetiology of childhood-onset hearing loss. Disease prevention has been achieved by our research on antibiotic-associated deafness, public awareness of risk to health and hearing has been raised, and we have increased public engagement through debate on scientific and social issues. We have also influenced public policy on ethics of genetic testing for deafness with our research resulting in improved quality, accessibility and acceptability of genetic services among many hard-to-reach groups (deafblind, culturally Deaf, and the Bangladeshi population of East London).