The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial‐like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well‐established association of NS with malignant tumors, especially childhood hemato‐oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.

Source: American Journal of Medical Genetics Part A - December 22, 2017 Category: Genetics & Stem Cells Authors: Frederike L. Harms, Malik Alawi, David J. Amor, Tiong Y. Tan, Goran Cuturilo, Christina Lissewski, Julia Brinkmann, Denny Schanze, Kerstin Kutsche, Martin Zenker Tags: CLINICAL REPORT Source Type: research