Atrioventricular canal defect in patients with RASopathies.
Congenital heart defects affect 60-85% of patients with RASopathies. We analysed the clinical and molecular characteristics of atrioventricular canal defect in patients with mutations affecting genes coding for proteins with role in the RAS/MAPK pathway. Between 2002 and 2011, 101 patients with cardiac defect and a molecularly confirmed RASopathy were collected. Congenital heart defects within the spectrum of complete or partial (including cleft mitral valve) atrioventricular canal defect were diagnosed in 8/101 (8%) patients, including seven with a PTPN11 gene mutation, and one single subject with a RAF1 gene mutation. The only recurrent mutation was the missense PTPN11 c.124 A>G change (T42A) in PTPN11. Partial atrioventricular canal defect was found in six cases, complete in one, cleft mitral valve in one. In four subjects the defect was associated with other cardiac defects, including subvalvular aortic stenosis, mitral valve anomaly, pulmonary valve stenosis and hypertrophic cardiomyopathy. Maternal segregation of PTPN11 and RAF1 gene mutations occurred in two and one patients, respectively. Congenital heart defects in the affected relatives were discordant in the families with PTPN11 mutations, and concordant in that with RAF1 mutation. In conclusion, our data confirm previous reports indicating that atrioventricular canal defect represents a relatively common feature in Noonan syndrome. Among RASopathies, atrioventricular canal defect was observed to occur with higher prevalence among subjects with PTPN11 mutations, even though this association was not significant possibly because of low statistical power. Familial segregation of atrioventricular canal defect should be considered in the genetic counselling of families with RASopathies.
Department of Medical Genetics, Cytogenetics, Pediatric Cardiology, Bambino Gesù Pediatric Hospital, IRCCS, Piazza S. Onofrio 4, Rome, Italy.
Maria Cristina
MC
Digilio
Francesca
F
Romana Lepri
Maria Lisa
ML
Dentici
Alex
A
Henderson
Anwar
A
Baban
Maria Cristina
MC
Roberti
Rossella
R
Capolino
Paolo
P
Versacci
Cecilia
C
Surace
Adriano
A
Angioni
Marco
M
Tartaglia
Bruno
B
Marino
Bruno
B
Dallapiccola
D004694:Endocardial Cushion Defects / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies; D006330:Heart Defects, Congenital / Q000453:epidemiology / Q000235:genetics; D006343:Heart Septal Defects; D006801:Humans; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D020837:SOS1 Protein / Q000235:genetics
D020837:SOS1 Protein; D019908:Proto-Oncogene Proteins c-raf; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11