RASA2 – Noonan syndrome

Noonan syndrome (NS) is an autosomal dominant RASopathy characterized by short stature (HP:0004322), global developmental delay (HP:0001263), and congenital cardiac anomalies (HP:0001627). RASA2 (HGNC:9872) encodes a RAS GTPase-activating protein and was highlighted as a novel RASopathy gene in a multi-gene review (PMID:26446362). Targeted sequencing of 27 NS patients without mutations in known genes identified a loss-of-function variant, c.1531C>T (p.Arg511Cys), in one unrelated proband (PMID:25049390). Expression of p.Arg511Cys in heterologous cells caused increased RAS-ERK pathway activation, consistent with defective GAP-mediated RAS inactivation (PMID:25049390). No segregation data or additional unrelated cases have been reported, limiting genetic corroboration. Functional assays provide moderate support, but the association remains limited until further case series or segregation studies emerge.

Key take-home: RASA2 variants may underlie NS in patients negative for canonical gene mutations; inclusion in diagnostic panels is reasonable with confirmatory studies pending.

References

• Journal of human genetics • 2016 • Recent advances in RASopathies. PMID:26446362
• Proceedings of the National Academy of Sciences of the United States of America • 2014 • Next-generation sequencing identifies rare variants associated with Noonan syndrome. PMID:25049390

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