Noonan syndrome (NS) belongs to RASopathies and is an autosomal dominant genetic disorder characterized by distinct facial features, short stature, congenital heart defects and developmental delays. However, in many cases it occurs de novo. Pathogenic variants in several RasMAPK pathway genes have been found to contribute to the phenotype, the most prevalent gene (50% of cases) being PTPN11. The rest of the affected individuals harbour mutations in other genes among which the proto-oncogene RAF1 is quite rare (only 3-17% of cases). RAF1 encodes a MAP3K that plays an essential role in cell division, differentiation and apoptosis. Mutations in this gene are associated with Noonan sy. 5 and Leopard sy. 2. Moreover, the majority of patients with RAF1 pathogenic variants manifest cardiac involvements, especially HCM (hypertrophic cardiomyopathy).
The goal of the study was genetic screening for RAF1 mutations in a Hungarian HCM cohort.
We screened 133 HCM patients (81 men, 52 women, average age: 45±15 years) using Next Generation Sequencing. RAF1 gene was also included in the 103 HCM genes panel.
Out of 133 HCM patients included in the study, 2 carried rare pathogenic variants in RAF1 gene that are indicative of NS: p.Ser257Leu in exon 7, and p.Leu633Val in exon 18. The first missense mutation was identified in a 1 year old girl and it’s clustered in the CR2 domain of the RAF1 protein known for its regulatory role. Several reports in the literature describe this mutation as highly pathogenic. The second mutation was identified in a newborn boy without a typical manifestation of NS but with a complex cardiac phenotype including severe obstructive hypertrophic cardiomyopathy, pulmonary stenosis and atrial septal defect. Family screening revealed that the mutation occurred de novo, further reinforcing its pathogenicity.
RAF1 pathogenic gene variants are rare cause of typical HCM and may be suspected in syndromic disease or with complex cardiac phenotypes.
The goal of the study was genetic screening for RAF1 mutations in a Hungarian HCM cohort.
We screened 133 HCM patients (81 men, 52 women, average age: 45±15 years) using Next Generation Sequencing. RAF1 gene was also included in the 103 HCM genes panel.
Out of 133 HCM patients included in the study, 2 carried rare pathogenic variants in RAF1 gene that are indicative of NS: p.Ser257Leu in exon 7, and p.Leu633Val in exon 18. The first missense mutation was identified in a 1 year old girl and it’s clustered in the CR2 domain of the RAF1 protein known for its regulatory role. Several reports in the literature describe this mutation as highly pathogenic. The second mutation was identified in a newborn boy without a typical manifestation of NS but with a complex cardiac phenotype including severe obstructive hypertrophic cardiomyopathy, pulmonary stenosis and atrial septal defect. Family screening revealed that the mutation occurred de novo, further reinforcing its pathogenicity.
RAF1 pathogenic gene variants are rare cause of typical HCM and may be suspected in syndromic disease or with complex cardiac phenotypes.
