Neurodevelopmental Comorbidities and Novel Population-based Mutations in Ethnic Patients with Neurofibromatosis Type 1

A BSTRACT Background: Neurofibromatosis type 1 (NF1) is a frequently occurring hereditary syndrome that affects 1 in 2500–3000 people worldwide. It causes a broad spectrum of clinical features such as dermatological manifestations, skeletal issues, and a predisposition to both noncancerous and cancerous tumors, such as malignant peripheral nerve sheath tumors and optic gliomas. NF1 is caused by mutations in the NF1 gene, which often lead to the loss of neurofibromin, a tumor suppressor protein. Around half of the cases result from de novo mutations. Given the variable symptoms of NF1 and its role in malignancy, understanding the genetic mechanisms behind these differences is crucial for improving personalized treatment and prognosis. Materials and Methods: In this research, we employed whole-exome sequencing to investigate patients in the Turkish Cypriot population who were suspected of having NF1, along with an analysis of their clinical symptoms. Results: Five distinct mutations were identified, with the most common being an in-frame deletion in exon 37 (NM₀01042492. 3: c. 5030TCTATA 1 p. Ile1679Tyr1680del, rs1135402868). Other variants included a frameshift mutation in exon 43 (NM₀01042492. 3: c. 6590₆591del p. Phe2197fs, rs2069707755), a nonsense mutation in exon 49 (NM₀01042492. 3: c. 7194C>G p. Tyr2398Ter, rs2070073649), and deletion of the 17q11. 2 region. A novel variant in exon 25 (NM₀01042492. 3: c. 3209₃210del p. Gln1070ArgfsTer18) was also discovered in a patient with café-au-lait spots and breast cancer, and her son with numerous café-au-lait spots, a lesion on the globus pallidus, mental problems, and short stature. Conclusion: These results emphasize the variability of NF1 mutations and the significance of next-generation sequencing in improving diagnostic sensitivity.