PHENOTYPIC CONSEQUENCES AND THE MALIGNANCY RISK IN FAMILIAL NOONAN SYNDROME DUE TO A RARE P.S427G RAF1 MUTATION

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Ras/MAPK pathway dysregulation causes Noonan syndrome (NS) and human cancers.
• RAF1 germline mutations are identified in NS, but malignancy incidence remains unreported.
• Somatic RAF1 mutations are observed in various cancers, including therapy-related acute myeloid leukemia (t-AML).

Purpose of the Study:

• To report a familial case of Noonan syndrome with a rare RAF1 germline mutation.
• To investigate the association between this specific RAF1 germline mutation and cancer development.
• To provide insights for genetic counseling regarding RAF1 alterations.

Main Methods:

• Case report of an adult female patient with Noonan syndrome and her affected mother.
• Genetic analysis to identify RAF1 germline mutation c.1279A>G (p.S427G).
• Review of existing literature on RAF1 mutations in NS and cancer.

Main Results:

• The familial Noonan syndrome case presented the rare RAF1 germline mutation p.S427G.
• This mutation, previously reported as somatic in t-AML, was found in a familial NS cohort without malignancy.
• This is the second reported familial case of Noonan syndrome with this specific RAF1 mutation.

Conclusions:

• Carrying a germline RAF1 mutation may not be associated with an increased risk of tumor development.
• The findings are significant for understanding the role of RAF1 in both germline disorders and somatic cancers.
• This study contributes to genetic counseling and management strategies for patients with RAF1 alterations.