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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.
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.
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.
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.
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 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.
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.
Our research has established that Trimethylaminuria (TMAU) — a rare and distressing disorder where affected individuals excrete large amounts of odorous trimethylamine (TMA) in their breath, sweat and urine — is a genetic disorder, and is not, as previously thought, due to poor hygiene. This has transformed understanding in the medical community and the wider public of why some people have an extremely unpleasant `fishy' body odour, and has been crucial to helping individuals with TMAU who often suffer social isolation, rejection, depression and higher than normal suicide rates. The findings have led to genetic diagnosis and genetic counselling for TMAU in the UK, Europe, USA and Canada and the publication of guidelines for the diagnosis and treatment of the disorder.
Keratins are major cytoskeletal proteins of epithelial cells. Pioneering research at the University of Dundee led by Prof Irwin McLean FRSE and Prof Birgit Lane FRSE showed the association of keratin mutations with genetic skin fragility disorders. This has dramatically changed the diagnosis of inherited skin disorders and has directly translated into improved clinical management of patients both in the UK and internationally. Further work on this disease has resulted in the first clinical trial using siRNA for a skin condition.
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.