PO11 Novel RAF 1 variant associated with Noonan Syndrome and Hypertrophic Cardiomyopathy

Noonan Syndrome can be associated with congenital heart defects and/or hypertrophic cardiomyopathy (HCM). Mutations in RAF1 gene occur in approximately 5% of patients, with HCM present in about 85% of these cases. We describe a previously unreported RAF1 gene variant associated with familial HCM and Noonan syndrome. An infant with abnormal prenatal screening (nuchal translucency of 7mm in the first trimester) was born at term, and was initially diagnosed with coarctation of the aorta, anomalous systemic venous drainage, and multiple muscular ventricular septal defects. He underwent surgery for coarctation of the aorta and an anomalous venous connection in the first month of life (a Waldhausen operation was performed along with correction of the venous anomaly). Subsequently, he required balloon angioplasty twice for re-coarctation of the aorta at 4th and 8th months of age. At the age of 12 months he was also diagnosed with hypertrophic cardiomyopathy with features of non-compaction confirmed later on cardiac magnetic resonance imaging (CMR). The recent CMR (08.2024) showed HCM with a maximal left ventricular wall thickness of 17 mm. Clinically the patient presented with Noonan syndrome features (prominent forehead, webbed neck, pectus excavatum) which got more pronounced with age. In his family history, the patient’s father had HCM, and underwent a heart transplant. His mother was treated for coarctation of the aorta. Genetic testing of the patient and his father revealed a novel, previously undescribed RAF1 c998G>T(p.Arg333Leu) variant, which was not present in his mother. Both clinical and phenotypical features of the father and child correspond with Noonan syndrome type 5, which is caused by RAF1 mutations. This variant has been reported by two laboratories as a variant of unknown significance; however, the clinical status of the affected patients was not provided. In patients with Noonan Syndrome harboring RAF1 variants, missense mutations are commonly observed, including the variant we report. The variant is located in the Intrinsically Disordered Region (IDR), a region in which mutations associated with Noonan Syndrome have been previously described as pathogenic. Furthermore, the variant we describe segregated with the disease. Therefore, our report sheds new light on this RAF1 variant in the context of its familial occurrence.