Prevalence of pathogenic and likely pathogenic variants in the RASopathy genes in patients who have had panel testing...

Area of Science:

• Genetics
• Cardiology
• Developmental Biology

Background:

• RASopathies are developmental disorders stemming from RAS-MAPK pathway genetic variants.
• Cardiomyopathy, particularly hypertrophic cardiomyopathy (HCM), is a significant clinical manifestation of RASopathies.
• HCM can be an initial indicator of RASopathy in affected individuals.

Purpose of the Study:

• To determine the prevalence of pathogenic or likely pathogenic variants in RAS pathway genes among patients with cardiomyopathy.
• To assess the diagnostic yield of RASopathy genes in a cardiomyopathy cohort, especially those with HCM.

Main Methods:

• Retrospective analysis of 74 patients who underwent cardiomyopathy gene panel testing.
• Evaluation of variants in 12 key RAS pathway genes (BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, SHOC2, SOS1).
• Categorization of cardiomyopathy types including HCM, dilated cardiomyopathy (DCM), and others.

Main Results:

• Four patients (5.41% of the total cohort) had pathogenic/likely pathogenic variants in RAS genes (HRAS, PTPN11, RAF1).
• All four identified patients had HCM as the indication for genetic testing.
• The prevalence of RASopathy gene variants in the HCM subgroup was 12.5% (4 out of 32 patients).

Conclusions:

• RASopathy-associated genes are a relevant cause of cardiomyopathy, particularly HCM.
• Inclusion of RASopathy genes in multi-gene cardiomyopathy panels may enhance diagnostic yield for HCM patients.
• Genetic testing for RAS pathway variants should be considered in individuals presenting with HCM.