Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation

Abstract

Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P value<0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (P<0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (P<0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

Figure 1

PS among individuals with NFNS according to mutation type. (a) An increased rate of non-truncating mutations is seen in individuals with NFNS compared with the general NF1 population (12/29 (41%) of patients with NFNS compared with 19.4% (326/1681) in a large NF1 cohort. (b) Stratifying the NFNS patients by their mutation type showed that among individuals with NFNS and PS 88.9% (8/9) had non-truncating mutations, whereas only 21% (4/19) of individuals with NFNS without PS had non-truncating mutations.

Figure 2

The frequency of non-truncating mutations in 11 unreported cases NF1 and (+) PS. 73% (8/11) of individuals with NF1 and PS were found to have intragenic non-truncating mutations compared with 19% in the general NF1 population.