A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation.

Noonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.

Deciphering the pathogenic role of rare RAF1 heterozygous missense mutation in the late-presenting DDH.

Background: Developmental Dysplasia of the Hip (DDH) is a skeletal disorder where late-presenting forms often escape early diagnosis, leading to limb and pain in adults. The genetic basis of DDH is not fully understood despite known genetic predispositions. Methods: We employed Whole Genome Sequencing (WGS) to explore the genetic factors in late-presenting DDH in two unrelated families, supported by phenotypic analyses and in vitro validation. Results: In both cases, a novel de novo heterozygous missense mutation in RAF1 (c.193A>G [p.Lys65Glu]) was identified. This mutation impacted RAF1 protein structure and function, altering downstream signaling in the Ras/ERK pathway, as demonstrated by bioinformatics, molecular dynamics simulations, and in vitro validations. Conclusion: This study contributes to our understanding of the genetic factors involved in DDH by identifying a novel mutation in RAF1. The identification of the RAF1 mutation suggests a possible involvement of the Ras/ERK pathway in the pathogenesis of late-presenting DDH, indicating its potential role in skeletal development.

RAF-1 Mutation Associated with a Risk for Ventricular Arrhythmias in a Child with Noonan Syndrome and Cardiovascular Pathology.

Introduction: Noonan syndrome (NS) is a dominant autosomal disease, caused by mutations in genes involved in cell differentiation, growth and senescence, one of them being RAF1 mutation. Congenital heart disease may influence the prognosis of the disease. Case presentation: We report a case of an 18 month-old female patient who presented to our institute at the age of 2 months when she was diagnosed with obstructive hypertrophic cardiomyopathy, pulmonary infundibular and pulmonary valve stenosis, a small atrial septal defect and extrasystolic arrhythmia. She was born from healthy parents, a non-consanguineous marriage. Due to suggestive phenotype for NS molecular genetic testing for RASopathies was performed in a center abroad, establishing the presence of RAF-1 mutation. Following rapid progression of cardiac abnormalities, the surgical correction was performed at 14 months of age. In the early postoperative period, the patient developed episodes of sustained ventricular tachycardia with hemodynamic instability, for which associated treatment was instituted with successful conversion to sinus rhythm. At 3-month follow-up, the patient was hemodynamically stable in sinus rhythm. Conclusions: The presented case report certifies the importance of recognizing the genetic mutation in patients with NS, which allows predicting the severity of cardiac abnormalities and therefore establishing a proper therapeutic management of these patients.