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<p>Pathogenic variants in <i>RAF1</i> are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases. Nonetheless, <i>RAF1</i>-related NS is often associated with severe clinical features, particularly hypertrophic cardiomyopathy (HCM). Although initial studies highlighted the occurrence of genotype-phenotype correlations, a comprehensive analysis specifically focused on <i>RAF1</i> variants is still lacking. We conducted a retrospective observational study combining newly collected cases of <i>RAF1</i>-related NS from a national multicenter retrospective cohort with systematically reviewed cases from&#xa0;a literature search. Variants were classified by protein domain, while the most recurrent variant, p.Ser257Leu, was analyzed separately to assess variant- and domain-specific phenotype correlations. A total of 203 cases were included. Variants in the CR2 domain accounted for 83% of cases, with p.Ser257Leu alone representing 53%. HCM was observed in 80.1% of affected individuals, confirming its role as the predominant cardiac manifestation in <i>RAF1</i>-related NS; neurodevelopmental features were reported in 44.5% of patients. The prevalence of clinical features varied significantly according to variant location. HCM was markedly more frequently associated with CR2 variants (89.4%) and in subjects heterozygous for the p.Ser257Leu change (94.2%) compared with non-CR2 variants (37.1%). Conversely, neurodevelopmental features were more common in patients with non-CR2 variants (69.2%) than in those with CR2 variants (38.2%) or p.Ser257Leu (29.4%). CR2 and p.Ser257Leu variants were associated with earlier age at diagnosis and increased mortality. Our findings confirm and document more comprehensively domain- and variant-specific phenotypes in <i>RAF1</i>-related NS, emphasizing the importance of variant-level interpretation in clinical management and genetic counseling.</p>

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Domain-specific phenotypic profiles in RAF1-related Noonan syndrome

  • 期刊论文

  • 发表日期：

    2026年1月8日

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  • Andrea Gazzin,
  • Marta Calvo,
  • Federico Rondot,
  • Giuseppe Reynolds,
  • Chiara Leoni,
  • Marcello Niceta,
  • Maria Lisa Dentici,
  • Maria Cristina Digilio,
  • Francesca Lepri,
  • Emanuele Monda,
  • Ilaria Carelli,
  • Eva Trevisson,
  • Iris Scala,
  • Giorgia Mancano,
  • Elena Andreucci,
  • Franco Stanzial,
  • Francesco Brancati,
  • Giuseppe Zampino,
  • Luigi Tarani,
  • Roberto Paparella,
  • Diana Carli,
  • Anna Maria Villar,
  • Elena Banaudi,
  • Stefania Massuras,
  • Simona Cardaropoli,
  • Paola Daniele,
  • Elena Airulo,
  • Chiara Riggi,
  • Giulio Calcagni,
  • Giovanni Battista Ferrero,
  • Giuseppe Limongelli,
  • Alessandro De Luca,
  • Marco Tartaglia,
  • Alessandro Mussa

摘要

Pathogenic variants in RAF1 are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases. Nonetheless, RAF1-related NS is often associated with severe clinical features, particularly hypertrophic cardiomyopathy (HCM). Although initial studies highlighted the occurrence of genotype-phenotype correlations, a comprehensive analysis specifically focused on RAF1 variants is still lacking. We conducted a retrospective observational study combining newly collected cases of RAF1-related NS from a national multicenter retrospective cohort with systematically reviewed cases from a literature search. Variants were classified by protein domain, while the most recurrent variant, p.Ser257Leu, was analyzed separately to assess variant- and domain-specific phenotype correlations. A total of 203 cases were included. Variants in the CR2 domain accounted for 83% of cases, with p.Ser257Leu alone representing 53%. HCM was observed in 80.1% of affected individuals, confirming its role as the predominant cardiac manifestation in RAF1-related NS; neurodevelopmental features were reported in 44.5% of patients. The prevalence of clinical features varied significantly according to variant location. HCM was markedly more frequently associated with CR2 variants (89.4%) and in subjects heterozygous for the p.Ser257Leu change (94.2%) compared with non-CR2 variants (37.1%). Conversely, neurodevelopmental features were more common in patients with non-CR2 variants (69.2%) than in those with CR2 variants (38.2%) or p.Ser257Leu (29.4%). CR2 and p.Ser257Leu variants were associated with earlier age at diagnosis and increased mortality. Our findings confirm and document more comprehensively domain- and variant-specific phenotypes in RAF1-related NS, emphasizing the importance of variant-level interpretation in clinical management and genetic counseling.