RRAS2 – Noonan Syndrome

RRAS2, a member of the Ras subfamily of small GTPases, has emerged as an important gene implicated in Noonan syndrome. Several independent case reports and multi‐patient studies have described RRAS2 mutations in patients with Noonan syndrome, where the clinical presentation includes hallmark features such as abnormal heart morphology, hydrocephalus, Dandy‑Walker malformation, short stature, and additional dysmorphic findings. These studies report de novo and recurrent missense variants, including the recurrent c.212G>A (p.Gly71Glu) change observed in multiple patients (PMID:31130282). The converging evidence from distinct cohorts supports a robust genetic association with this disorder.

The genetic evidence is reinforced by clear segregation patterns observed in affected individuals and their families. Although most of the reported mutations are de novo, multi‐patient studies documented RRAS2 variants in at least 23 probands (PMID:34648682) and demonstrated recurrence across independent families. Variant spectrum analysis across studies has identified several missense changes, as well as duplications, affecting highly conserved residues near the nucleotide binding pocket. The use of comprehensive genetic panels and whole‐exome sequencing have been instrumental in confirming the pathogenic role of these variants.

In addition to robust genetic data, experimental studies have provided solid functional evidence supporting the pathogenicity of RRAS2 variants in Noonan syndrome. Functional assays demonstrate that these mutations lead to a gain‑of‑function effect causing hyperactivation of the MAPK pathway. In various cellular and animal models, mutant RRAS2 exhibits increased association with downstream effectors, resulting in abnormal signaling that correlates with the severe clinical phenotype observed clinically (PMID:38601074). This functional concordance with disease pathology further validates the genetic findings.

While conflicting evidence exists in the broader context of oncogenic RRAS2 mutations in cancer, the clinical studies focusing on Noonan syndrome have consistently reported a distinct spectrum of clinical features and de novo events that specifically support its role in this developmental disorder. The functional studies also distinguish the hyperactivation observed in Noonan syndrome from other tumorigenic processes, indicating a genotype–phenotype specificity that is critical for diagnostic decision‑making. Therefore, the overall evidence robustly supports the pathogenic association between RRAS2 and Noonan syndrome.

Integrating genetic and experimental data, the evidence clearly indicates a strong association between RRAS2 mutations and Noonan syndrome. The studies provide multiple lines of evidence from case reports, segregation analysis, and functional validations, justifying a ClinGen gene–disease association category of Strong. Additional evidence exists that exceeds the ClinGen scoring maximum, further emphasizing the clinical utility of RRAS2 testing in severe and atypical presentations of Noonan syndrome.

Key take‑home sentence: Comprehensive genetic and functional analyses strongly support the use of RRAS2 mutation testing in the diagnostic workup for Noonan syndrome, enabling targeted clinical management and therapeutic decisions.

References

• American journal of medical genetics. Part A • 2022 • The RRAS2 pathogenic variant p.Q72L produces severe Noonan syndrome with hydrocephalus: A case report PMID:34648682
• European journal of medical genetics • 2023 • Clinical analysis of Noonan syndrome caused by RRAS2 mutations and literature review PMID:36460282
• American journal of human genetics • 2019 • Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome PMID:31130282
• American journal of human genetics • 2019 • Germline-Activating RRAS2 Mutations Cause Noonan Syndrome PMID:31130285
• Frontiers in genetics • 2024 • Functional analysis of RRAS2 pathogenic variants with a Noonan-like phenotype PMID:38601074

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