RAF1 – Noonan syndrome with multiple lentigines

RAF1 has been established as an autosomal dominant cause of Noonan syndrome with multiple lentigines (NSML), also known as LEOPARD syndrome, characterized by lentigines, cardiac conduction defects, craniofacial dysmorphism, and sensorineural deafness. Genetic studies in PTPN11‐negative cohorts revealed RAF1 variants in multiple unrelated NSML probands, supporting a robust gene–disease association.

Inheritance is autosomal dominant. A de novo missense variant, c.770C>T (p.Ser257Leu), was identified in a 14-year-old female with NSML and craniosynostosis (PMID:31145547). Additional RAF1 variants have been reported in at least six unrelated NSML cases without PTPN11 or BRAF mutations, including hotspot CR2 domain substitutions in two of six LEOPARD patients in a cohort of 237 individuals (PMID:17603483).

Case series and cohort studies have described at least seven probands harboring missense variants clustered in the conserved region 2 (CR2) of RAF1 (including p.Ser257Leu, p.Ser259Cys, p.Ser259Phe, and p.Val263Gly). These variants co-segregate with NSML features such as hypertrophic cardiomyopathy (HP:0001639) and lentigines, with no evidence of alternative genetic etiologies (PMID:17603483; PMID:31145547).

Functional studies demonstrate that CR2 mutations abrogate inhibitory phosphorylation at Ser259, disrupt 14-3-3 binding, and enhance RAF1 kinase activity and downstream ERK signaling. Knock-in of CR2 variants in cell models recapitulates hyperactive MAPK pathway signaling consistent with NSML pathogenesis (PMID:20052757).

No conflicting evidence has been reported; RAF1 mutations are consistently identified in PTPN11/BRAF‐negative NSML cohorts and are absent in large control populations. Together, genetic and experimental data support a strong gene–disease validity for RAF1 in NSML.

Key take-home: RAF1 should be included in diagnostic gene panels for NSML to enable definitive molecular diagnosis, guide management of cardiac and cutaneous manifestations, and inform family counseling.

References

• Nature Genetics • 2007 • Gain‐of‐function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. PMID:17603483
• Human Mutation • 2010 • Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. PMID:20052757
• American Journal of Medical Genetics Part A • 2019 • RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis. PMID:31145547

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