NRAS – Costello syndrome

Germline NRAS mutations have been extensively evaluated in patients with RASopathies, including Costello syndrome (CS; MONDO:0009026), without positive findings. In a cohort of two CS/CFC patients, targeted sequencing of HRAS, KRAS, NRAS and other RAS-MAPK genes revealed no NRAS variants in the CS case (PMID:20030748). Similarly, in a follow-up study of 80 RASopathy‐suspected individuals, including CS phenotypes, high–throughput NGS yielded no pathogenic NRAS alterations among confirmed CS mutations (PMID:24451042). No segregation of NRAS variants with CS traits has been reported.

Functional studies of NRAS focus on somatic activating mutations in malignancies and do not support a role for germline NRAS dysfunction in CS pathogenesis. The absence of NRAS variants in CS cohorts and lack of relevant mechanistic data argue against clinical testing of NRAS for CS diagnosis or management.

Key take-home: NRAS is not implicated in Costello syndrome and should not be included in germline diagnostic panels for CS.

References

• Pediatrics international • 2010 • Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway. PMID:20030748
• BMC medical genetics • 2014 • Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. PMID:24451042

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