NRAS – Noonan syndrome with multiple lentigines

Noonan syndrome with multiple lentigines is an autosomal dominant RASopathy characterised by multiple lentigines, cardiac anomalies, and facial dysmorphism. Germline gain-of-function variants in RAS-MAPK pathway genes, including NRAS and Noonan syndrome with multiple lentigines, underlie this disorder.

A targeted next-generation sequencing panel assessing 10 RASopathy genes in a training set of 80 patients with clinically suspected RASopathies identified pathogenic variants in PTPN11, SOS1, RAF1, BRAF, HRAS, KRAS, and NRAS with a 100% confirmation rate by Sanger sequencing ([PMID:24451042]). In this cohort, NRAS gain-of-function variants were detected in a subset of probands, all exhibiting autosomal dominant transmission and confirmed by orthogonal methods ([PMID:24451042]).

Segregation data remain limited; co-segregation of NRAS alleles with disease was observed in index families but the number of affected relatives has not been fully enumerated ([PMID:24451042]).

Reported NRAS variants in RASopathies include canonical missense changes at hotspot codons such as c.35G>T (p.Gly12Val) ([PMID:15046639]). These variants disrupt GTP hydrolysis, leading to constitutive NRAS activation.

Functional studies of oncogenic NRAS variants (p.Gly12Val) demonstrate strong transforming activity in cellular models and enhanced MAPK pathway signaling, supporting a gain-of-function mechanism consistent with Noonan syndrome-associated pathogenesis ([PMID:15046639]).

Overall, the gene–disease association between NRAS and Noonan syndrome with multiple lentigines is classified as Limited given evidence from a single cohort, few confirmed probands, and a lack of extensive segregation or in vivo RASopathy-specific functional models. Genetic and functional evidence tiers are Limited. Inclusion of NRAS in diagnostic panels for RASopathies is recommended to improve early clinical diagnosis and management.

Key take-home: NRAS gain-of-function variants should be considered in molecular testing for Noonan syndrome with multiple lentigines, enabling timely diagnosis and tailored clinical management.

References

• BMC medical genetics • 2014 • Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. PMID:24451042
• Journal of carcinogenesis • 2004 • Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. PMID:15046639

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