Abstract
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.
Highlights
Neurofibromatosis type 1 (NF1, MIM #162200), known as von Recklinghausen disease, is one of the most common autosomal dominant disorders with multisystem involvement
Mutation analysis was performed on germline DNA, and only mutations in the classical splice sites or known to alter splicing were classified as splicing mutations; the prevalence of this type of mutation could be an underestimation since it is well established that many neurofibromatosis type 1 (NF1) mutations alter splicing through non-canonical splicing sites [39]
Present data confirm the significant frequency of congenital heart disease (CHD) in patients with NF1, mostly represented by pulmonary valve stenosis and mitral valve anomalies, and more rarely by septal defects or other
Summary
Neurofibromatosis type 1 (NF1, MIM #162200), known as von Recklinghausen disease, is one of the most common autosomal dominant disorders with multisystem involvement. NF1 affects approximately 1/2000 live births [1], and is characterized by considerable inter- and intra-familial clinical variability [2]. Major features of the disease include café-au-lait spots (CaLS), skinfold freckling (SF), Lisch nodules (LN), neurofibromas (NF), typical bone abnormalities, and optic pathway glioma (OPG) [2]. NF1 encodes neurofibromin, a protein with tumor suppressor function belonging to the family of GTPase activating proteins (GAPs). Neurofibromin is expressed in several cells, including neurons, and Schwann and glial cells, and has an important modulatory role in the control of cellular proliferation, differentiation, apoptosis, and migration. Promoting the conversion from active GTP-bound RAS to inactive GDP-bound
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
