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

1
UOS Diagnosi Genetica Molecolare, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy
2
Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Pediatric Hospital and Research Institute, 00165 Rome, Italy
3
Department of Translational Medical Science, Section of Pediatrics, Federico II University, 80100 Naples, Italy
4
Department of Pediatrics, Sapienza University of Rome, 00161 Rome, Italy
5
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
6
Department of Dermatology and Venereology, Sapienza University of Rome, Policlinico Umberto I, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2019, 10(9), 675; https://doi.org/10.3390/genes10090675
Received: 27 July 2019 / Revised: 30 August 2019 / Accepted: 1 September 2019 / Published: 4 September 2019
(This article belongs to the Special Issue Neurofibromatosis 1 Genetics)
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. View Full-Text
Keywords: neurofibromatosis type 1; congenital heart disease; pulmonary valve stenosis; non-truncating mutation; Noonan syndrome neurofibromatosis type 1; congenital heart disease; pulmonary valve stenosis; non-truncating mutation; Noonan syndrome
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Pinna, V.; Daniele, P.; Calcagni, G.; Mariniello, L.; Criscione, R.; Giardina, C.; Lepri, F.R.; Hozhabri, H.; Alberico, A.; Cavone, S.; Morella, A.T.; Mandile, R.; Annunziata, F.; Di Giosaffatte, N.; D’Asdia, M.C.; Versacci, P.; Capolino, R.; Strisciuglio, P.; Giustini, S.; Melis, D.; Digilio, M.C.; Tartaglia, M.; Marino, B.; De Luca, A. Prevalence, Type, and Molecular Spectrum of NF1 Mutations in Patients with Neurofibromatosis Type 1 and Congenital Heart Disease. Genes 2019, 10, 675.

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