A new gene test will greatly improve the speed and clarity of diagnosis for a complex range of genetic disorders known as RASopathies.
The new test has been developed by molecular diagnostic testing company NewGene in collaboration with the South West Thames Regional Genetics Service at St George’s Healthcare NHS Trust in London, the specialist centre for Noonan Syndrome and associated hereditary disorders in the UK.
Noonan Syndrome and related disorders (rasopathies) are autosomal dominant congenital syndromes. These disorders are characterised by facial dysmorphism, a wide spectrum of cardiac disease, postnatal reduced growth, ectodermal and skeletal defects, and variable cognitive deficits.
Although some features are more frequently associated with particular syndromes, variable presentations make it difficult to provide a definitive clinical diagnosis. Correctly identifying the disorder is essential to ensure that appropriate care and monitoring is provided and to preclude unnecessary investigations.
The research laboratories at St George’s have worked for over 10 years to clone the genes for Noonan Syndrome. Currently genetic testing of suspected Noonan cases is carried out on a gradual basis by testing for one disorder or gene and then another until a mutation is identified to confirm the diagnosis. This is both time consuming and costly and delays the determination of the best clinical care pathway for patients.
The new work carried out by NewGene and the specialists at St George’s has resulted in the development of a new one step test that utilises Roche 454 sequencing to provide large scale parallel screening of all 12 genes associated with Noonan disorders in one panel. This includes all coding exons of 11 genes plus exon 2 of SHOC2.
Multiple samples with known mutations previously identified by the Sanger sequencing technique have been run alongside normal control samples in blind screening trials to validate the new sequencing assay.
Before the availability of molecular testing, making a clinical diagnosis was difficult and required many specialist tests including clotting and cardiac investigations. Molecular testing has simplified the process of making a diagnosis. However, due to the significant clinical overlap of the Noonan spectrum disorders, targeting the correct genes has remained problematic.
This comprehensive new assay will now allow a refined diagnosis to be made more quickly than has been possible previously. This approach will also be far cheaper to the NHS than screening all available genes in separate assays.
A positive test result will provide a definite diagnosis of the syndrome in question as the mutation spectrum has been well defined and no cases of non-penetrance have been identified. Importantly, as a positive result will also determine which disorder is applicable, medical interventions appropriate for that specific disorder can be highlighted more quickly.
Although a positive result will not negate the need for standard clinical investigations, it will enable clinical management to be more targeted reducing the need for batteries of expensive and protracted specialist investigations, many of which require ward admission.
This will assist in decision making regarding growth hormone treatment, provision of special education for delayed development, treatment using fresh frozen plasma to avoid life threatening haemorrhage and haematological monitoring.
Professor Michael Patton, Medical Advisor for the Noonan Syndrome Association UK said “Since the discovery of new genes in the RAS MAPK pathway it has become increasingly difficult and expensive to undertake full genetic testing for Noonan syndrome, but the development of the next generation sequencing test at NewGene and St George’s hospital is a major advance in the diagnosis of Noonan syndrome”.
Noonan spectrum disorders affect around 1 in 1,000 live births. The early identification of a pathogenic mutation will also facilitate informative genetic counselling and confirmation testing in other affected individuals in the family. A definitive diagnosis would allow families early use of patient support groups such as the Noonan Syndrome Association (NSA).
St George’s is the only centre registered with UKGTN to offer analysis for Noonan and Leopard syndromes and is likely to provide the full national need for these and other related syndromes of the RAS MAPK pathway.
Sources: St George’s Healthcare NHS Trust & NewGene