Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome

Area of Science:

• Genetics
• Cardiology
• Pediatrics

Background:

• Noonan syndrome (NS) commonly presents with cardiac abnormalities like congenital heart diseases (CHD), pulmonary valve stenosis, and hypertrophic cardiomyopathy (HCM).
• Molecular diagnostics facilitate earlier and more precise identification of NS patients, including those with subtle or atypical presentations.

Purpose of the Study:

• To investigate genotype-phenotype associations in Noonan syndrome (NS) concerning cardiac abnormalities.
• To explore the relationship between genetic mutations and the need for catheter or surgery-based interventions in NS patients.
• To identify potential prognostic indicators based on genetic profiles.

Main Methods:

• Enrolled 22 children with confirmed molecular diagnosis of NS and cardiovascular abnormalities between January 2019 and December 2021.
• Conducted a comprehensive review of echocardiography, electrocardiogram results, whole-exome sequencing data, and intervention records.
• Analyzed genotype-phenotype correlations and intervention outcomes.

Main Results:

• Common electrocardiogram abnormalities included QTc prolongation and ventricular hypertrophy. Pulmonary valve dysplasia with stenosis (68.2%) and atrial septal defect (50%) were the most frequent cardiac findings.
• Mutations in PTPN11 and RAF1 were most common (27% each). Specific genes correlated with distinct phenotypes: RIT1, SOS1, PTPN11, SOS2 with pulmonary valve stenosis; RAF1 and BRAF with HCM.
• BRAF and RAF1 genotypes were associated with poorer prognosis, potentially requiring multiple interventions for severe pulmonary stenosis or HCM.

Conclusions:

• Identifying causal genes in NS patients allows for evaluation of genotype-cardiac phenotype relationships and disease prognosis.
• Understanding these associations can guide the development of targeted therapeutic approaches for Noonan syndrome.
• Genetic profiling may aid in predicting the need for interventions and long-term management strategies.