Genotypic Variability in Neurofibromin Domains to Predict Phenotypic Outcomes of Neurofibromatosis type 1: Evidence from a Prospective Clinical-Genetic Cohort

Abstract Background Neurofibromatosis type 1 (NF1), caused by mutations in the NF1 gene, exhibits significant clinical heterogeneity. Recent studies have identified potential correlations between specific phenotypes and neurofibromin domains of the mutated NF1 gene; however, research into these specific associations remains limited.Purpose This study aimed to investigate the correlation between clinical phenotypes and specific neurofibromin domains in a prospectively characterized cohort of NF1 patients..Methods Clinical data from patients diagnosed with NF1 at our institution's Neurofibromatosis Multidisciplinary Team (MDT) clinic were prospectively collected. Clinical manifestations including café-au-lait macules, freckles, cutaneous neurofibromas, plexiform neurofibromas, Lisch nodules, skeletal abnormalities, optic pathway gliomas, and other associated lesions were documented comprehensively. All patients underwent genetic testing through whole exome sequencing or multiple-gene panel test. The neurofibromin domains affected by the identified mutations were investigated. Genotype-phenotype correlation analysis was performed, with particular focus on the neurofibromin domains affected by mutations in the NF1 gene.Results A total of 74 patients were included in the study. The average age was 13.8 years old, and 50% (37/74) were male. Additionally, 98.6%(73/74) of the patients had six or more café-au-lait macules, 47.2%(35/74) had cutaneous neurofibromas, and 25.6% (19/74) had plexiform neurofibromas. Lisch nodules were present in 21.6% (16/74) of patients, skeletal abnormalities in 21.6% (16/74). Subcutanious nodular neurofibroma were found in (18/74 ). The NF1 gene exhibited various mutation type, including missense variation, in-frame deletion, nonsense variation, frameshift mutation, copy number variation, and splicing variation. Specifically, variations affecting protein Kinase C (PKC) domain were observed in 11 cases (14.9%), cysteine-Rich Domain(CSRD) in 26 cases (35.1%), tuberin Binding Domain(TBD) domain in 25 cases (33.7%) ,GTPase-activating protein related domain (GRD) in 34 cases (45.9%), Sec14-PH domain in 37 cases (50%), and C-terminal domain (CTD) domain in 55 cases (74.3%). Statistical analysis revealed no significant differences in phenotype across multiple domains (p > 0.05), except for a higher incidence of nodular neurofibromas in patients with PKC domain variants (p = 0.008). The cumulative number of involving domains did not predict the severity of clinical symptoms.Conclusions Despite comprehensive analysis, predicting the full range and severity of NF1 phenotypes based solely on neurofibromin domains remains challenging. Our finding of an association between PKC domain variants and nodular neurofibromas highlights the potential for domain-specific correlations with particular phenotypic features, warranting further investigation in larger cohorts to refine genotype-phenotype relationships and improve clinical prognostication.