EH@ESC_2015

CARDIOLOGY EUROPEAN HOSPITAL  Vol 24 Issue 4/15 10 An extra asset in the diagnostic toolkit UK progresses genetic testing to identify FH New cardiac genetic testing panels Familial hypercholesterolaemiaA ground-breaking genetic testing programme for an inherited and potentially-deadly high cholesterol condition has been extended to more United Kingdom health trusts, Mark Nicholls reports. Report: Mark Nicholls As new cardiac genetic testing panels become available, cardiologists have been warned not to lose sight of the importance of comprehensive clini- cal evaluation. While genetic testing is helping to identify more people at risk of inherited conditions, experts stress they are only part of the diag- nostic toolkit. This was outlined in a session entitled ‘The new cardiac genetic testing panels: implications for the clinical cardiologist’ held during the British Cardiovascular Society Conference in Manchester this June. With the emergence of new genet- ic tests for cardiac disease, Professor Cliff Garratt raised issues ‘the cardi- ologist needs to know’ in making the modern diagnosis. Sanger Sequencing remains the standard to confirm a single genetic variant but new tests – next gen- eration sequencing – which can be applied to a large number of genes, are now facilitating more testing, more cheaply and in the same time- scale with panels of genes. Garratt, who is Professor of Cardiology at the Institute of Cardiovascular Sciences, Professor of Cardiology at Manchester University and Hon Consultant Cardiologist at Central Manchester University Foundation Trust, explained: ‘We can have them highly targeted at 5-15 genes for LQT, for example, or a less targeted panel for 20 genes, though the disadvantage of The faulty gene associated with Familial hypercholesterolaemia (FH) is found in an estimated one in 200 UK families – making this the coun- try’s most common genetic mutation, with possibly as many as 320,000 people affected, including around 68,000 people under 18 years old. FH is caused by a genetic fault that leaves people with abnormally high cholesterol, which significantly increases their risk of heart disease, including a heart attack and, on aver- age, shortens life expectancy by 20 to 30 years if untreated. If one person in a family is found with FH, on average half of their brothers and sisters and half of their children will also have the faulty gene and be at high risk of early heart disease. Most FH cases are never diagnosed, putting them at significantly higher risk of dying young from a heart attack. Now funding of over £900,000 from the British Heart Foundation (BHF) is enabling the availability of FH testing in five further UK areas. With a simple DNA blood test, a spe- cialist nurse can identify whether an individual with a clinical diagnosis of FH carries the faulty gene. If discov- ered, they are then referred for family cascade testing with all immediate first-degree relatives also invited for testing and treatment at their local clinic. If diagn#osed, early statin treat- ment, lifestyle advice and careful monitoring, mean that an individual’s life expectancy goes up to match the average of the general population. The additional FH cascade testing funding – extended to University Hospitals Birmingham, York Teaching Hospitals Foundation Trust, NHS Western Isles, Gloucestershire Hospitals NHS Foundation Trust, and the Royal Brompton & Harefield NHS Foundation Trust – was announced in June at the British Cardiovascular Society Conference. These follow the initial roll-out across eight sites – Royal Free London NHS Foundation Trust, Guys and St Thomas National Health Service Foundation Trust, South Yorkshire Cardiothoracic Centre, Greater Manchester and Cheshire Cardiac and Stroke Network, University Hospitals Bristol NHS Foundation Trust, City Hospitals Sunderland NHS Foundation Trust, NHS Grampian / North of Scotland Cardiac Network, and University Hospital Southampton NHS Foundation Trust – which has already identified 500+ FH people. Jo Whitmore, the FH Clinical Lead at the BHF, said: ‘If high cholesterol is left unchecked, fatty materials can build up in your arteries, increasing your risk of heart disease. The prob- lem with FH is that it dramatically increases the LDL cholesterol in the person’s blood, causing a heart attack, commonly at a very young age. We know that cascade testing within families works, and the challenge is now to engage with NHS organ- isations and commissioners across Britain so that no family falls through the cracks. ‘FH is easily treated, so no family should have to go through the pain of seeing a loved one have a heart attack that could have been prevented.’ The National Institute for Health and Care Excellence (NICE) estimates that if 50% of the predicted relatives of people with FH are diagnosed and treated, the NHS could save £1.7 mil- lion per year on healthcare for heart disease by preventing cardiovascular events. From a clinical commissioning per- spective, FH has not been on the ‘radar’ of general healthcare com- missioners, but has not been seen as small enough to do specialist commis- sioning either. However, screening is a cost effec- tive option, Whitmore confirms: ‘For the first person in the family identi- fied the cost is about £200 for the DNA test but, once you’ve identified the gene you are looking for, the test comes down to £75 for other family members.’ the panel approach is that you have the problem of background genetic noise.’ Advances in genetic and genomic technology are enabling many more patients with a rare disease to bene- fit from genetic tests, either to estab- lish or confirm a diagnosis; or assess the genetic status of other family members and gene panel tests are now making it possible to test simultaneously all the genes known to be associated with a condition. Despite having the benefits of genetic testing, Garratt issued a clear warning that, whilst genetic testing is proving valuable, it is not an alternative to making a clinical diagnosis. ‘It will not solve your clinical problems but will help man- agement of patients who you have a proper diagnosis for,’ he said. During the same session Dr Shehla Mohammed outlined the work of the UKGTN (United Kingdom Gene Testing Network) in the evaluation process for genetic tests. The role of UKGN is strategic; it involves healthcare commissioning and evaluating new genetic tests for clinical utility and validity with screening for 698 disorders, 872 genes and 46 panel tests. ‘It’s about promoting equity of access of genet- ic tests for individuals who have, or are, at risk of genetic disorders,’ Mohammed explained. UKGTN works with 30 member laboratories across the UK, many affiliated to regional genetic cen- tres and some linked with special- ist services and follows the ACCE model process for evaluating genet- ic tests of: Analytic Validity; Clinical Validity; Clinical Utility; and Legal and Ethical and Social implications. ‘The reasons for doing genetic test- ing is for diagnosis, treatment, prog- nosis and management, pre-sympto- matic diagnostic testing and genetic risk assessment,’ Mohammed added. ‘The UKGTN promotes high quality, equitable and appropriately identi- fied genetic tests.’ It has the capabil- ity to deliver effective cascade test- ing in inherited cardiac disorders. Dr Kay Metcalfe, NHS Consultant Clinical Geneticist at St Mary’s Hospital Manchester, discussed panel testing for Sudden Cardiac Death SCD syndromes. Underlining Garratt’s point, she added: ‘Family screening helps iden- tify those at risk, but the challenges of the exome and genome sequenc- ing approach are the large amount of data generated. Genetic testing is probabilistic and forms part of a comprehensive clinical evaluation.’ Dr Paul Clift, from Queen Elizabeth Hospital, Birmingham, spoke about genetic testing in the context of Marfan syndrome and other familial thoracic aortic aneu- rysm syndromes but stressed the importance of physical and clinical assessment in such conditions in association with genetic testing. According to Clift, Marfan remains a clinical diagnosis but fibrillian-1 (FNB1) gene testing aids that diag- nosis and there are advantages with panel testing giving rapid genotyp- ing allowing a detailed management strategy for patients. ‘Panel testing in aortopathy allows for early genotyping for suspected hereditary aortopathy, risk stratifies management strategy for patients and families.’ Cliff Garratt is Professor of Cardiology at the Institute of Cardiovascular Sciences, Professor of Cardiology at Manchester University and Hon Consultant Cardiologist at Central Manchester University Foundation Trust. (See profile on page 6) Jo Whitmore has worked within cardiovascular nursing for over 20 years in roles that include managing a Coronary Care Unit and being a specialist nurse in Cardiology involved in acute chest pain management and thrombolysis. More recently she has been involved in a number of projects in relation to CVD, working for the British Heart Foundation Clinical Lead for Familial Hypercholesterolaemia sites. She is a member of the Primary Care CVD Leadership Forum in the UK, which works alongside Public Health England, NHS England, Royal College of General Practitioners and the British Heart Foundation. Copyright:Shutterstock/Horoscope Copyright:Shutterstock/RAJCREATIONZS

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