OBJECTIVE. Noonan syndrome is a clinically homogeneous but genetically heterogeneous condition. Type 1 Noonan syndrome is defined by the presence of a mutation in the PTPN11 gene, which is found in ∼40% of the cases. Phenotype descriptions and cardiac defects from cohorts with Noonan syndrome were delineated in the “pregenomic era.” We report the heart defects and links to gene dysfunction in cardiac development in a large cohort of patients with type 1 Noonan syndrome.

METHODS. This was a retrospective, multicenter study based on clinical history, pictures, and medical and cardiologic workup over time. Data were collected by referral geneticists. Mutation screening was performed by direct sequencing of exons 2, 3, 4, 7, 8, 12, and 13 and their intron-exon boundaries, which harbor 98% of identified mutations the PTPN11 gene.

RESULTS. A PTPN11 gene mutation was identified in 104 (38.25%) of 274 patients with Noonan syndrome. Heart defect was present in 85%. The most prevalent congenital 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 secundum type, were significantly associated with the identification of a mutation in the PTPN11 gene. Ventricular septal defect and most left-sided heart defects showed a trend toward overrepresentation in the group without a mutation.

CONCLUSION. We compared our data with previous series and integrated the comprehension of molecular PTPN11 gene dysfunction in heart development.

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