Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis

Objective: Neurofibromatosis type 1 (NF1, #162200) is a common neurological disorder with de novo or inherited germline mutations of the Neurofibromin (NF1, *613113). The purpose of this study is to increase the limited knowledge of NF1 in a small population-based dataset. Materials and Methods: This study enrolled patients with clinically suspected NF1 referred to the Kayseri Training and Research Hospital, Medical Genetics Department, between 2015 and 2017. The local ethics committee approved this study. Next-generation sequencing was performed for the genetic analysis. The genetic, demographic, and clinical features of the participants were characterized. Results: A total of 79 cases of NF1 were included. Of these cases, 40 were male, and 39 were female. The mean age was 11.9 years, and most were younger than 18 years. The most common complaint was café au lait macules. The 61 (77.3%) patients had pathogenic variants, and 16 (26.2%) were novel. Mostly affected mutation sites were exonic regions (n=54, 88.5%). The most common mutated exon was exon 38 (n=7, 11.5%), and most of the detected mutations were nonsense mutations (31%). Conclusion: It is one of Türkiye’s largest NF1 study groups, where all exons of the NF1 gene were analyzed. This study contributes novel variants to the literature. There was no mutational hotspot region, and no significant relationship between genotype and phenotype was observed. Further studies and large sample sizes are required to better understand the relationship between NF and genetic changes.

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1. Allaway RJ, Gosline SJC, La Rosa S, Knight P, Bakker A, Guinney J, et al. Cutaneous neurofibromas in the genomics era: current understanding and open questions. Br J Cancer 2018; 118(12): 1539–48.
2. Tsipi M, Poulou M, Fylaktou I, Kosma K, Tsoutsou E, Pons MR,et al. Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA. J Neurol Sci 2018; 395: 95–105.
3. Ulusal SD, Gürkan H, Atlı E, Özal SA, Çiftdemir M, Tozkır H, et al. Genetic analyses of the NF1 Gene in Turkish neurofibromatosis Type I patients and definition of three novel variants. Balkan J Med Genet 2017; 20(1): 13–20.
4. Castellanos E, Rosas I, Negro A, Gel B, Alibés A, Baena N, et al. Mutational spectrum by phenotype: panel-based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café-aulait macules. Clin Genet 2020; 97(2): 264–75.
5. Wu-Chou YH, Hung TC, Lin YT, Cheng HW, Lin JL, Lin CH, et al. Genetic diagnosis of neurofibromatosis type 1: targeted next- generation sequencing with Multiple Ligation-Dependent probe amplification analysis. J Biomed Sci 2018; 25(1): 72.
6. Karaconji T, Whist E, Jamieson RV, Flaherty MP, Grigg JRB. Neurofibromatosis Type 1: Review and Update on Emerging Therapies. Asia Pac J Ophthalmol (Phila) 2019; 8(1): 62–72.
7. Philpott C, Tovell H, Frayling IM, Cooper DN, Upadhyaya M. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics 2017; 11(1): 13.
8. Rubin JB, Gutmann DH. Neurofibromatosis type 1 - a model for nervous system tumour formation? Nat Rev Cancer 2005; 5(7): 557–64.
9. Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 2015; 15(5): 290–301.
10. Kang E, Kim YM, Seo GH, Oh A, Yoon HM, Ra YS, et al. Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. J Hum Genet 2020; 65(2):79–89.
11. Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotypephenotype study in neurofibromatosis type 1. Hum Mutat 2020; 41(1): 299–315.
12. Koczkowska M, Chen Y, Callens T, Gomes A, Sharp A, Johnson S, et al. Genotype-phenotype correlation in NF1: Evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848. Am J Hum Genet 2018; 102(1): 69–87.
13. N Abdel-Aziz N, Y El-Kamah G, A Khairat R, R Mohamed H, Z Gad Y, El-Ghor AM, et al. Mutational spectrum of NF1 gene in 24 unrelated Egyptian families with neurofibromatosis type 1. Mol Genet Genomic Med 2021; 9(12): e1631.
14. Kaçar AG, Kılınc Oktay B, Çınar Özel S, Ocak S, Güneş N, Uludağ Alkaya D, et al. Neurofibromatosis Type 1 in children: A single-center experience. Turk Arch Pediatr 2021; 56(4): 339–43.
15. Bahsi T, Saat H. Neurofibromatosis Type 1 molecular diagnosis in Turkish patients. Gazi Med J 2020; 31(3): 406–9.
16. Solmaz AE, Isik E, Atik T, Ozkinay F, Onay H. Mutation spectrum of the NF1 gene and genotype-phenotype correlations in Turkish patients: Seventeen novel pathogenic variants. Clin Neurol Neurosurg 2021; 208: 106884.
17. Palma Milla C, Lezana Rosales JM, López Montiel J, Andrés Garrido LD, Sánchez Linares C, Carmona Tamajón S, et al. Neurofibromatosis type I: mutation spectrum of NF1 in spanish patients. Ann Hum Genet 2018; 82(6): 425–36.
18. Terzi YK, Oguzkan S, Anlar B, Aysun S, Ayter S. Neurofibromatosis: novel and recurrent mutations in Turkish patients. Pediatr Neurol 2007; 37(6): 421–5.
19. No authors listed. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis 1988; 1(3): 172–8.
20. Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med 2010; 12(1): 1–11.
21. Origone P, De Luca A, Bellini C, Buccino A, Mingarelli R, Costabel S, et al. Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients. Hum Mutat 2002;20:74–5.
22. Incesoy Ozdemir S, Citak Kurt AN, Özlü SG. Clinical and radiological features of neurofibromatosis Type 1: Single center’s experience. ANKARA Med J 2020; 20(1): 224–33.

APA	Kiraz A, GÜMÜŞ H, Balta B, Erdogan M, güven a, savranlar a, celik s, Kumandaş S, Karaman Z, Ozdemir Y, Gümüş G, Bayram N, Per H (2023). Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. , 152 - 158. 10.14744/etd.2022.90023
Chicago	Kiraz Aslihan,GÜMÜŞ HAKAN,Balta Burhan,Erdogan Murat,güven ahmet sami,savranlar ahmet,celik serkan fazli,Kumandaş Sefer,Karaman Zehra Filiz,Ozdemir Yesim,Gümüş Gülsüm,Bayram Nurettin,Per Hüseyin Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. (2023): 152 - 158. 10.14744/etd.2022.90023
MLA	Kiraz Aslihan,GÜMÜŞ HAKAN,Balta Burhan,Erdogan Murat,güven ahmet sami,savranlar ahmet,celik serkan fazli,Kumandaş Sefer,Karaman Zehra Filiz,Ozdemir Yesim,Gümüş Gülsüm,Bayram Nurettin,Per Hüseyin Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. , 2023, ss.152 - 158. 10.14744/etd.2022.90023
AMA	Kiraz A,GÜMÜŞ H,Balta B,Erdogan M,güven a,savranlar a,celik s,Kumandaş S,Karaman Z,Ozdemir Y,Gümüş G,Bayram N,Per H Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. . 2023; 152 - 158. 10.14744/etd.2022.90023
Vancouver	Kiraz A,GÜMÜŞ H,Balta B,Erdogan M,güven a,savranlar a,celik s,Kumandaş S,Karaman Z,Ozdemir Y,Gümüş G,Bayram N,Per H Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. . 2023; 152 - 158. 10.14744/etd.2022.90023
IEEE	Kiraz A,GÜMÜŞ H,Balta B,Erdogan M,güven a,savranlar a,celik s,Kumandaş S,Karaman Z,Ozdemir Y,Gümüş G,Bayram N,Per H "Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis." , ss.152 - 158, 2023. 10.14744/etd.2022.90023
ISNAD	Kiraz, Aslihan vd. "Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis". (2023), 152-158. https://doi.org/10.14744/etd.2022.90023

APA	Kiraz A, GÜMÜŞ H, Balta B, Erdogan M, güven a, savranlar a, celik s, Kumandaş S, Karaman Z, Ozdemir Y, Gümüş G, Bayram N, Per H (2023). Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. Erciyes Medical Journal, 45(2), 152 - 158. 10.14744/etd.2022.90023
Chicago	Kiraz Aslihan,GÜMÜŞ HAKAN,Balta Burhan,Erdogan Murat,güven ahmet sami,savranlar ahmet,celik serkan fazli,Kumandaş Sefer,Karaman Zehra Filiz,Ozdemir Yesim,Gümüş Gülsüm,Bayram Nurettin,Per Hüseyin Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. Erciyes Medical Journal 45, no.2 (2023): 152 - 158. 10.14744/etd.2022.90023
MLA	Kiraz Aslihan,GÜMÜŞ HAKAN,Balta Burhan,Erdogan Murat,güven ahmet sami,savranlar ahmet,celik serkan fazli,Kumandaş Sefer,Karaman Zehra Filiz,Ozdemir Yesim,Gümüş Gülsüm,Bayram Nurettin,Per Hüseyin Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. Erciyes Medical Journal, vol.45, no.2, 2023, ss.152 - 158. 10.14744/etd.2022.90023
AMA	Kiraz A,GÜMÜŞ H,Balta B,Erdogan M,güven a,savranlar a,celik s,Kumandaş S,Karaman Z,Ozdemir Y,Gümüş G,Bayram N,Per H Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. Erciyes Medical Journal. 2023; 45(2): 152 - 158. 10.14744/etd.2022.90023
Vancouver	Kiraz A,GÜMÜŞ H,Balta B,Erdogan M,güven a,savranlar a,celik s,Kumandaş S,Karaman Z,Ozdemir Y,Gümüş G,Bayram N,Per H Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. Erciyes Medical Journal. 2023; 45(2): 152 - 158. 10.14744/etd.2022.90023
IEEE	Kiraz A,GÜMÜŞ H,Balta B,Erdogan M,güven a,savranlar a,celik s,Kumandaş S,Karaman Z,Ozdemir Y,Gümüş G,Bayram N,Per H "Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis." Erciyes Medical Journal, 45, ss.152 - 158, 2023. 10.14744/etd.2022.90023
ISNAD	Kiraz, Aslihan vd. "Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis". Erciyes Medical Journal 45/2 (2023), 152-158. https://doi.org/10.14744/etd.2022.90023