Prevalence, Type, and Molecular Spectrum of NF1 Mutations in Patients with Neurofibromatosis Type 1 and Congenital Heart Disease

Valentina Pinna, Paola Daniele, Giulio Calcagni, Lucio Mariniello, Roberta Criscione, Chiara Giardina, Francesca Romana Lepri, Hossein Hozhabri, Angela Alberico, Stefania Cavone, Annunziata Tina Morella, Roberta Mandile, Francesca Annunziata, Niccolò Di Giosaffatte, Maria Cecilia D'Asdia, Paolo Versacci, Rossella Capolino, Pietro Strisciuglio, Sandra Giustini, Daniela MelisMaria Cristina Digilio, Marco Tartaglia, Bruno Marino, Alessandro De Luca

Research output: Contribution to journalArticlepeer-review


The aim of this study was to assess the prevalence and type of congenital heart disease (CHD) and the associated mutation spectrum in a large series of patients with neurofibromatosis type 1 (NF1), and correlate the mutation type with the presence and subgroups of cardiac defects. The study cohort included 493 individuals with molecularly confirmed diagnosis of NF1 for whom cardiac evaluation data were available. CHD was reported in 62/493 (12.6%) patients. Among these patients, 23/62 (37.1%) had pulmonary valve stenosis/dysplasia, 20/62 (32.3%) had mitral valve anomalies, and 10/62 (16.1%) had septal defects. Other defects occurred as rare events. In this NF1 subcohort, three subjects carried a whole-gene deletion, while 59 were heterozygous for an intragenic mutation. A significantly increased prevalence of non-truncating intragenic mutations was either observed in individuals with CHD (22/59, 37.3%) or with pulmonary valve stenosis (13/20, 65.0%), when compared to individuals without CHD (89/420, 21.2%) (p = 0.038) or pulmonary valve stenosis (98/459, 21.4%) (p = 0.002). Similarly, patients with non-truncating NF1 mutations displayed two- and six-fold higher risk of developing CHD (odds ratio = 1.9713, 95% confidence interval (CI): 1.1162-3.4814, p = 0.0193) and pulmonary valve stenosis (odds ratio = 6.8411, 95% CI: 2.6574-17.6114, p = 0.0001), respectively. Noteworthy, all but one patient (19/20, 95.0%) with pulmonary valve stenosis, and 18/35 (51.4%) patients with other CHDs displayed Noonan syndrome (NS)-like features. Present data confirm the significant frequency of CHD in patients with NF1, and provide further evidence for a higher than expected prevalence of NF1 in-frame variants and NS-like characteristics in NF1 patients with CHD, particularly with pulmonary valve stenosis.

Original languageEnglish
Issue number9
Publication statusPublished - Sep 4 2019


  • congenital heart disease
  • neurofibromatosis type 1
  • non-truncating mutation
  • Noonan syndrome
  • pulmonary valve stenosis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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