Molecular pathology and clinical presentation of Slovenian patients with isolated cardiomyopathy and pathogenic variants in RASopathy-associated genes

Introduction

RASopathies are a group of multisystem disorders caused by germline pathogenic variants in genes encoding proteins of the RAS-MAPK signalling pathway. Around 80% of patients with RASopathies have cardivascular disorders, including structural heart diseases and cardiomyopathies (CMs). As RASopathies exhibit variable expressivity, clinical features such as mildly expressed distinctive facial features, minor heart defects and/or short stature may be overlooked in adult patients with RASopathies and CM, resulting in a diagnosis of isolated CM. Cohort studies revealed that a small percentage of patients with HCM have a molecular pathology in RASopathy-associated genes, whereas reports on patients with other types of CM and findings in these genes are limited.

Purpose

To study the role of RASopathy-associated genes in molecular pathology of Slovenian patients with CMs.

Methods

An internal CIGM clinical registry was used to identify all patients referred for isolated CM and who underwent NGS genetic testing between July 2019 and July 2025. Genetic data were reinterpreted to identify variants in RASopathy-associated genes.

Results

A total of 503 patients with CMs were identified, of whom 206 (40.9%) had hypertrophic CM (HCM), 187 (37.2%) dilated CM (DCM), 37 (7.4%) arrhythmogenic CM (ACM), 23 (4.6%) noncompaction CM (NCC), 4 (0.8%) restrictive CM and 46 (9.1%) clinically undefined CM (CU CM). Molecular pathology was identified in 145 (28.8%) patients, more specifically in 65 (31.6%) with HCM, 57 (30.4%) with DCM, 14 (37.8%) with ACM, 6 (26.1%) with NCC and 3 (6.5%) with CU CM.

A pathogenic variant in a RASopathy-associated gene was identified in 4 patients (2.8% of genotype-positive); in patient 1 (P1) and patient 2 (P2) in the KRAS gene, and in patient 3 (P3) and patient 4 (P4) in the PTPN11 gene. The variant was present in all cell lines of P2 and P4, whereas it was present as somatic mosaicism in P1 and P3 (allelic fraction via NGS: 30% and 36%).

P1 and P3 presented with DCM, P2 with ACM and P4 with HCM, receiving their diagnosis at 60 (P1), 51 (P2), 49 (P3) and 17 (P4) years of age. P1 underwent mitral and tricuspid valve reconstruction and atrial septal defect closure, while P2 underwent ablation due to an episode of ventricular tachycardia. Both had an ICD implanted. None of the patients exhibited any other obvious phenotypic features of RASopathies. P1 and P3 had a family history of heart disease, while P2 and P4 did not.

Conclusions

We identified a pathogenic variant in RASopathy-associated genes in 2.8% of genotype-positive patients referred due to isolated CM. Two patients had variants in the KRAS gene, and two in the PTPN11 gene. Two patients harboured the variant in an apparent somatic mosaicism. Establishing a diagnosis in these patients is particularly important for the appropriate clinical and reproductive management of those patients.