Atrioventricular canal defect in patients with RASopathies

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• RASopathies are genetic disorders associated with congenital heart defects (CHDs), affecting 60-85% of patients.
• Atrioventricular canal defect (AVCD) is a specific type of CHD that warrants further investigation within RASopathies.

Purpose of the Study:

• To analyze the clinical and molecular characteristics of atrioventricular canal defects in patients with RASopathies.
• To investigate the association between specific gene mutations in the RAS/MAPK pathway and AVCD.

Main Methods:

• Retrospective analysis of 101 patients with molecularly confirmed RASopathy and cardiac defects between 2002 and 2011.
• Detailed clinical and molecular characterization, including genetic sequencing and familial segregation analysis.

Main Results:

• Eight out of 101 patients (8%) had AVCD spectrum defects, with seven harboring PTPN11 mutations and one a RAF1 mutation.
• The PTPN11 c.124A>G (T42A) missense mutation was the only recurrent mutation identified.
• AVCD was associated with other cardiac anomalies in four patients and showed variable familial segregation patterns.

Conclusions:

• Atrioventricular canal defect is a significant feature in Noonan syndrome and other RASopathies.
• PTPN11 mutations are frequently associated with AVCD in RASopathies, though statistical significance was limited by sample size.
• Familial segregation of AVCD should be a consideration in genetic counseling for RASopathy families.