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

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.

Keywords: Noonan syndrome; congenital heart disease; neurofibromatosis type 1; non-truncating mutation; pulmonary valve stenosis.

Figure 1

Prevalence of non-truncating mutations in individuals with intragenic NF1 mutations stratified according to the presence/absence of an unspecified congenital heart disease (CHD), or solely based on the presence/absence of pulmonary valve stenosis (PVS), and prevalence of CHD and PVS in individuals with non-truncating NF1 intragenic mutations. (a) Increased prevalence of NF1 non-truncating mutations observed among neurofibromatosis type 1 (NF1) individuals with CHD compared with those without CHD. (b) Increased prevalence of CHD among NF1 individuals with intragenic non-truncating mutations respect to patients with NF1 intragenic truncating mutations. (c) Increased rate of NF1 non-truncating mutations among NF1 individuals with PVS respect to those without PVS. (d) Prevalence of PVS in individuals with NF1 intragenic non-truncating mutations respect to those with intragenic truncating mutations.

Figure 2

Mutation spectrum of the NF1 gene in the study cohort. Schematic view of the proportion of nonsense mutations, frameshift indels, splice site changes, intragenic copy number variations (CNVs), whole-gene deletions (WGDs), and missense variants/in-frame indels in (a) 493 individuals with diagnosis of NF1, (b) 431 individuals with diagnosis of NF1 without CHD, (c) 62 individuals with diagnosis of NF1 with CHD, and (d) 21 individuals with diagnosis of NF1 with PVS.