Genetic Test Improves Noonan Syndrome Diagnosis

This includes all coding exons of 11 genes plus exon 2 of SHOC2.

Molecular testing company NewGene (Newcastle-Upon-Tyne, United Kingdom) developed the new test in collaboration with the South West Thames Regional Genetics Service at St George’s Healthcare NHS Trust (Tooting, United Kingdom).

Noonan Syndrome and related disorders (rasopathies) are autosomal dominant congenital syndromes. These disorders are characterized by facial dysmorphism, a wide spectrum of cardiac disease, postnatal reduced growth, ectodermal and skeletal defects, and variable cognitive deficits.

Variable presentations of the syndrome 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.

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.

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.

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.

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 nonpenetrance 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.

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.”

Related Links:
NewGene
South West Thames Regional Genetics Service at St George’s Healthcare NHS Trust