Mutations in the PTPN11 Gene The Spectrum of Cardiac Anomalies in Noonan Syndrome as a Result of

ABSTRACT OBJECTIVE. Noonan syndrome is a clinically homogeneous but genetically heteroge-neous condition. Type 1 Noonan syndrome is defined by the presence of amutation in the PTPN11 gene, which is found in 40% of the cases. Phenotypedescriptions and cardiac defects from cohorts with Noonan syndrome were delin-eated in the “pregenomic era.” We report the heart defects and links to genedysfunction in cardiac development in a large cohort of patients with type 1Noonan syndrome. METHODS. This was a retrospective, multicenter study based on clinical history,pictures, and medical and cardiologic workup over time. Data were collected byreferral geneticists. Mutation screening was performed by direct sequencing ofexons 2, 3, 4, 7, 8, 12, and 13 and their intron-exon boundaries, which harbor98% of identified mutations the PTPN11 gene. RESULTS. A PTPN11 gene mutation was identified in 104 (38.25%) of 274 patientswith Noonan syndrome. Heart defect was present in 85%. The most prevalentcongenital heart defects were pulmonary valve stenosis (60%), atrial septal defect,ostium secundum type (25%), and stenosis of the peripheral pulmonary arteries(in at least 15%). Pulmonary valve stenosis and atrial septal defect, ostium secun-dum type, were significantly associated with the identification of a mutation in the