Mapping the Genetic Landscape of Neurofibromatosis: Insights from a Multi-Generational Family Study

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition resulting from mutations in the NF1 tumor suppressor gene. Affected individuals exhibit pigmentary changes, including café-au-lait macules, skinfold freckling, and Lisch nodules, along with the development of dermal neurofibromas. Neurofibromas in the oral cavity predominantly affect the tongue and are typically present as nodular lesions. Objectives: To investigate the genetic etiology of neurofibromatosis in a large multigenerational family. Methods: The present genetic analysis involved six affected and two unaffected controls of the same family. Clinical evaluations and pedigree construction were carried out before the genetic analyses. Genomic DNA was isolated from blood samples. An exome research panel and targeted sequencing were performed to identify pathogenic variants. Segregation analysis was carried out to understand the inheritance pattern within the family. Results: The affected gene, NF1 (+) (Transcript - ENST00000358273), was identified through targeted sequencing. Variants in NF1+ were detected in a heterozygous state in severely affected maternal grandmother, maternal aunt, maternal uncle, mother, and less severely affected elder sister. Segregation analysis revealed an autosomal dominant pattern, with the variant absent in the unaffected father and unaffected sister. Phenotypic variability was observed among affected individuals, with distinctive oral manifestations contributing to the clinical presentation. Conclusion: Our findings establish NF1+ as the gene affected by this multigenerational family, indicating autosomal dominant inheritance of NF1. The identified pathogenic variants provide a basis for genetic counseling, aiding in clinical management.