Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective Study

Abstract

Background: Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder caused by pathogenic variants in the NF1 gene. Although genotype-phenotype correlation studies are increasing, robust clinically relevant correlations have remained limited. Methods: We conducted a retrospective analysis of data obtained from a cohort of 204 Hungarian individuals, with a mean age of 16 years (age range: 1-33 years). The data were collected over 15 years. Results: Among the cohort of 204 patients, 148 subjects fulfilled ≥2 criteria established by the National Health Institute. Genetic testing was performed in 70 patients, with an 82.8% detection rate, of which 13 patients were excluded. Among the remaining 45 pathogenic variants, 17 (37.7%) frameshift, 11 (24.4%) nonsense, 8 (17.8%) splice-site, 4 (8.9%) missense mutations, and 5 (11.11%) copy number variations (CNVs) were detected. Café-au-lait macules were present in all patients (100%). Intracranial malformations were the second most common feature (55.6%), followed by Lisch nodules (35.6%), neurofibromas (33.3%), and skeletal abnormalities (31.1%). Conclusions: In our cohort, patients with splice-site variants (8/45, 17.8%) demonstrated a notably more severe phenotype compared to findings reported in other studies, with a high prevalence of plexiform neurofibromas (37.5%), intracranial findings (62.5%), skeletal abnormalities (50%), Lisch nodules (50%), and even pseudarthrosis (25%). Correlating with the literature, missense variants represented a mild phenotype, while patients with microdeletion syndrome revealed a more severe phenotype.

Keywords: NF1 gene; NGS; genotype–phenotype analyses; rare diseases; splice-site mutations; type 1 neurofibromatosis.

Figure 1

Number of patients involved in our study.

Figure 2

Age and Gender Distribution in NF1 Patients of our Cohort: (a) Gender Distribution of our Cohort, (b) Gender Distribution of Patients with Positive Genetic Test, (c) Gender Distribution of Patients with Available Positive Mutation analyzed in the study, (d) Gender Distribution of Patients under 12 years of age, (e) Gender Distribution of Patients between 12 and 18 years, (f) Gender Distribution of Patients over 18 years of age.

Figure 3

Relative proportion of the different types of variants among the NF1-mutations identified.

Figure 4

Percentage distribution of the frequency of the most common NF1-related clinical features in the cohort of patients with positive test results.

Figure 5

Percentage distribution of the frequency of the most common NF1-related clinical features in the different variant types of our patients. (dark blue color) Frameshift (N = 17), (brown color) Nonsense (N = 11), (light blue color) Splice-Site (N = 8), (green color) CNV (N = 5), (red color) Missense (N = 4).