Novel Features of RASopathies: Liver Disease as an Emerging Phenotype
Alyssa L Rippert1,2, Alanna Strong1,3, Rebecca C Ahrens-Nicklas1,3
1Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
American Journal of Medical Genetics. Part A
|February 5, 2026
Summary
RASopathies, genetic conditions from RAS/MAPK pathway variants, frequently involve liver issues. Neonatal hyperbilirubinemia and cholestasis are common, particularly in infants with BRAF variants, necessitating liver disease screening.
Area of Science:
- Genetics
- Pediatrics
- Hepatology
Background:
- RASopathies are genetic disorders caused by variants in RAS/MAPK pathway genes.
- Liver involvement is recognized but not systematically studied in RASopathies.
- Lack of data hinders clinical guidance and screening for liver disease in these patients.
Purpose of the Study:
- To systematically characterize the spectrum and frequency of liver involvement in individuals with RASopathies.
- To identify specific RASopathy genotypes associated with particular liver pathologies.
- To inform clinical management and screening protocols for liver disease in RASopathy patients.
Main Methods:
- Retrospective analysis of 192 patients with molecularly confirmed RASopathy.
- Data abstraction from medical records for liver-related clinical information.
- Statistical analysis to determine the prevalence and risk factors for liver involvement.
Main Results:
- 36.5% of patients exhibited liver involvement.
- Neonatal hyperbilirubinemia occurred in 33.3%, with 24% requiring phototherapy (OR 7.1).
- Cholestasis was more frequent in patients with BRAF variants (OR 6.2).
Conclusions:
- RASopathies are strongly associated with neonatal liver disease, including hyperbilirubinemia and cholestasis.
- Liver function evaluation is recommended for infants with RASopathies.
- Individuals with BRAF variants may require closer monitoring for cholestasis.
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