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Background <p>Genetic mutations causing dysregulation of the RAS/mitogen-activated protein kinase pathway contribute to hypertrophic cardiomyopathy (HCM). Genotype-phenotype associations in this population remain poorly understood. This study aimed to evaluate the impact of RASopathy subtype on cardiovascular outcomes.</p> Methods <p>We included 24 patients diagnosed with RAS signaling pathway mutations and HCM (RAS-HCM) before age 18. Data on sociodemographic, prenatal, clinical, genetic, and echocardiographic parameters were retrospectively collected from medical records spanning 2004-2024. Death, heart failure (HF), transplant (Ts), and use of implantable cardioverter defibrillator (ICD) were also evaluated.</p> Results <p>Median age at HCM diagnosis was 0.42 years (IQR 7.1); median follow-up was 8.5 years. Patients were classified into Noonan syndrome (62.5%) and other RASopathies (37.5%). Pathogenic mutations were identified in <i>PTPN11</i> (38%), <i>RAF1</i> and <i>BRAF</i> (17% each), and <i>SOS1</i> and <i>RIT1</i> (13% each). Patients with Noonan syndrome underwent significantly more therapeutic strategies (<i>p</i> = 0.026). Increased end-diastolic interventricular septal thickness (IVSd) and left ventricular posterior wall thickness (LVPWd) were linked to the development of HF (<i>p</i> = 0.006, <i>p</i> = 0.007; respectively), while increased IVSd was associated with higher mortality (<i>p</i> = 0.013).</p> Conclusions <p>Echocardiographic parameters (IVSd and LVPWd), and RASopathy subtype may serve as prognostic indicators in pediatric RAS-HCM patients. Further studies are warranted to elucidate the underlying molecular mechanisms.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Demonstrates that RASopathy subtype may influence hypertrophic cardiomyopathy (HCM) progression and clinical outcomes in pediatric patients.</p> </ItemContent> <ItemContent> <p>Identifies end-diastolic interventricular septal thickness (IVSd) and left ventricular posterior wall thickness (LVPWd) as critical echocardiographic predictors of heart failure and cardiac mortality from early stages.</p> </ItemContent> <ItemContent> <p>Supports early genetic testing and echocardiographic monitoring to guide personalized care in pediatric RASopathies.</p> </ItemContent> </UnorderedList></p>

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Impact of RASopathy subtype on the early disease course of RASopathy-associated hypertrophic cardiomyopathy: clinical outcomes and genetic insights

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • José Luis López-Guillén,
  • Atilano Carcavilla,
  • Jesús Díez-Sebastián,
  • Emi Rikeros Orozco,
  • Marta Gambra-Arzoz,
  • Federico Gutiérrez Larraya,
  • Lucía Deiros-Bronte

摘要

Background

Genetic mutations causing dysregulation of the RAS/mitogen-activated protein kinase pathway contribute to hypertrophic cardiomyopathy (HCM). Genotype-phenotype associations in this population remain poorly understood. This study aimed to evaluate the impact of RASopathy subtype on cardiovascular outcomes.

Methods

We included 24 patients diagnosed with RAS signaling pathway mutations and HCM (RAS-HCM) before age 18. Data on sociodemographic, prenatal, clinical, genetic, and echocardiographic parameters were retrospectively collected from medical records spanning 2004-2024. Death, heart failure (HF), transplant (Ts), and use of implantable cardioverter defibrillator (ICD) were also evaluated.

Results

Median age at HCM diagnosis was 0.42 years (IQR 7.1); median follow-up was 8.5 years. Patients were classified into Noonan syndrome (62.5%) and other RASopathies (37.5%). Pathogenic mutations were identified in PTPN11 (38%), RAF1 and BRAF (17% each), and SOS1 and RIT1 (13% each). Patients with Noonan syndrome underwent significantly more therapeutic strategies (p = 0.026). Increased end-diastolic interventricular septal thickness (IVSd) and left ventricular posterior wall thickness (LVPWd) were linked to the development of HF (p = 0.006, p = 0.007; respectively), while increased IVSd was associated with higher mortality (p = 0.013).

Conclusions

Echocardiographic parameters (IVSd and LVPWd), and RASopathy subtype may serve as prognostic indicators in pediatric RAS-HCM patients. Further studies are warranted to elucidate the underlying molecular mechanisms.

Impact

Demonstrates that RASopathy subtype may influence hypertrophic cardiomyopathy (HCM) progression and clinical outcomes in pediatric patients.

Identifies end-diastolic interventricular septal thickness (IVSd) and left ventricular posterior wall thickness (LVPWd) as critical echocardiographic predictors of heart failure and cardiac mortality from early stages.

Supports early genetic testing and echocardiographic monitoring to guide personalized care in pediatric RASopathies.