NRAS – Noonan syndrome

Noonan syndrome is an autosomal dominant developmental disorder characterized by short stature, wide-set eyes (hypertelorism) and congenital heart defects. Germline activating variants in the Ras‐MAPK pathway, including NRAS, underlie a subset of Noonan syndrome cases. Clinical features often include hypertelorism (HP:0000316), abnormal heart morphology (HP:0001627) and short stature (HP:0004322).

Multiple independent reports have described missense NRAS variants in unrelated Noonan syndrome probands. A novel I24N variant was identified in an individual with classic NS features [PMID:21263000]. In a cohort of 115 mutation‐negative patients, three additional probands harbored Thr50Ile (c.149C>T (p.Thr50Ile)) and other NRAS substitutions [PMID:22855653]. Two further cases with Gly60Glu (c.179G>A (p.Gly60Glu)) were detected among 125 French patients [PMID:22887781], and a familial study confirmed inheritance of Gly60Glu in an affected parent and child [PMID:26467218]. Altogether, eight unrelated probands have been reported with NRAS missense variants.

Segregation analysis in one multigenerational family demonstrated co‐segregation of the Gly60Glu variant with NS features in two affected relatives [PMID:26467218], supporting an autosomal dominant inheritance.

All reported germline NRAS variants are missense substitutions (Ile24Asn, Gly12Ser, Gly12Val, Thr50Ile, Gly60Glu) that cluster in functional GTP‐binding domains, consistent with a gain‐of‐function mechanism.

Functional studies in zebrafish embryos showed that expression of N‐Ras I24N, Thr50Ile or Gly12Val induces gastrulation and cardiovascular defects resembling NS phenotypes. These defects are fully rescued by MEK inhibition, confirming pathogenic activation of Ras‐MAPK signaling by these variants [PMID:21263000].

In summary, germline missense NRAS variants cause Noonan syndrome via gain‐of‐function effects, with robust genetic and in vivo experimental evidence. NRAS testing should be included in diagnostic panels for RASopathy evaluation. Key take‐home: Activating NRAS mutations are a validated cause of Noonan syndrome, guiding genetic diagnosis and potential MEK‐targeted therapies.

References

• Disease models & mechanisms • 2011 • Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects PMID:21263000
• Molecular syndromology • 2012 • NRAS Mutations in Noonan Syndrome PMID:22855653
• American journal of medical genetics. Part A • 2012 • Constitutional NRAS mutations are rare among patients with Noonan syndrome or juvenile myelomonocytic leukemia PMID:22887781
• BMC medical genetics • 2015 • Mutation in NRAS in familial Noonan syndrome--case report and review of the literature PMID:26467218

Evidence Based Scoring (AI generated)