RASopathies

Genetic testing is clinically relevant for the following indications, including but not limited to:

• Children with suspected ; the van der Burgt clinical scoring system supports diagnostic decision-making
• Suspected or , particularly in young children where clinical features alone are inconclusive
• Apparent nonsyndromic hypertrophic cardiomyopathy where extra-cardiac RASopathy features may be unrecognised
• Fetal structural abnormalities on prenatal imaging suggestive of a RASopathy

Testing is typically requested by paediatricians, clinical geneticists, paediatric cardiologists and maternal-fetal medicine specialists.

Molecular testing is used when phenotypic overlap across the RASopathies makes the individual condition difficult to distinguish clinically, and it confirms the diagnosis suggested by established criteria. A precise genetic result supports clinical decision-making and enables specific management.

• A pathogenic or likely pathogenic variant establishes the specific molecular diagnosis, identifying the causative gene and condition within the RASopathy spectrum.
• A variant of uncertain significance (VUS) is an unclear finding: current evidence is insufficient to classify it as likely benign or likely pathogenic, and reanalysis can be offered as evidence accumulates.
• In other cases, no pathogenic variant is detected in the analysed genes; a pathogenic variant cannot, however, be entirely excluded, as the causative change may lie in a gene not yet linked to the condition or in a regulatory region that current methods cannot reliably capture.
• Each variant is classified according to ACMG/AMP criteria, incorporating disease- and gene-specific specifications developed by where available.

When a pathogenic variant is identified, it secures the specific RASopathy diagnosis and enables condition-specific management, including congenital heart disease and, where relevant, tumour surveillance. It informs prognosis and reproductive counselling. Because most RASopathies are autosomal dominant, an identified variant has implications for relatives, for whom cascade or predictive genetic testing can be considered.

is an important part of the testing process. It helps patients and families understand the test, interpret results, and make well-informed medical decisions, and it supports physicians in delivering informed care. Availability of genetic counselling services may vary by country. Please to check out access in your region.

Testing is performed using based multi-gene panels.

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