Balkan Journal of Medical Genetics

CASE REPORT FOR TWO SIBLINGS CARRYING NEUROFIBROMATOSIS TYPE 1 WITH A RARE NF1: c.5392C>T MUTATION
Sayın Kocakap DB, Gündüz Ö, Özer L, Durak M
*Corresponding Author: Associate Professor Derya B. Sayın Kocakap, Kırıkkale Üniversitesi Tıp Fakültesi Tıbbi Genetik AD, Ankara Yolu 7.km, 71450, Kırıkkale, Turkey. Tel.: +90-318-357-3300/5784. Fax: +90-318-225-2819. E-mail: dsayin@yahoo.com
page: 99

DISCUSSION

The NF1 gene spans 287 kb of chromosome 17q11.2 and comprises 57 constitutive and four alternatively spliced exons (9a,10a-2, 23a and 48a) [7]. To date, the Human Gene Mutation Database has documented more than 2450 disease-causing NF1 variants, of which 745 are missense/ nonsense [8]. In the Varsome database (https:// vas=rsome. com/gene/nf1), 26.1% of reported class 1 NF1 variants (328/1254) are nonsense mutations [9]. In our analysis, a C>T transition at nucleotide 5392 in exon 38, causing a premature termination codon at codon 1798 instead of a glutamine codon, was detected. Recently, Zhu et al. [10] reported a study of NF1 germline variants in patients with congenital pseudoarthrosis of the tibia (CPT). Screening 55 NF1 patients with CPT they found 44 NF1 variants, of which 25 were novel. They described a c.5392C>T, p.(Gln1798Ter) inherited mutation in one patient, but they did not present the patient’s clinical characteristics [10]. Here, we present two cases of NF1, a brother and a sister with c.5392C>T, p.Gln1798Ter mutation on the NF1 gene. Neurofibromatosis type 1 has great clinical variability even between affected individuals of the same family with variants were also analyzed and confirmed by Sanger sequencing (Figure 4) according to the manufacturer’s protocols. Briefly, the amplicons were analyzed by direct sequencing with ABI PRISM® 3500 (Life Technologies, Waltham, MA, USA). Analysis of sequence results was done by the Mutation Surveyor program (SoftGenetics). The primer sequences and polymerase chain reaction (PCR) conditions will be provided by the corresponding author upon request. the same mutation. Our represented cases of siblings also show inter-individual variation; they have different features of skin pigmentation, and the sister has an additional neural sheath tumor. The prominent lesions of the brother were relatively benign café au lait macules, but the sister also had a plexiform neurofibroma, estimated to have a lifetime risk of 5.0% for malignant transformation [11]. We speculate that modifier genes, as well as epigenetic and environmental changes, might be the cause of the clinical variability. Although NF1 is a monogenic disorder, its clinical variability is similar to multifactorial disorders and may be affected by epigenetic and environmental changes, modifier genes as well as second somatic mutations during tumorigenesis. As NF1 is expressed in a large variety of tissues, possible modifier genes have variable effects, such as actin cytoskeleton remodeling, cell signaling, intracellular trafficking, ubiquitylation, membrane localization, cell adhesion and neural differentiation [12]. In twin studies, it has been shown that plexiform neurofibromas tended to be less concordant, and it is explained by the two-hit hypothesis as many NF1-related tumors necessitate a second mutation on the wild-type NF1 allele [13]. Consistent with this view, the major phenotypic difference is plexiform neurofibroma between our cases. To the best of our knowledge, this is the first case report with detailed clinical findings of NF1 with NF1: c.5392C>T mutation. Although NF1: c.5392C>T is a nonsense mutation, predicted to cause premature termination and a truncated neurofibromin protein, the clinical course of NF1 in our patients and their family is benign. Even though there is great intra-familial and inter-familial variability in NF1 phenotypes, we can speculate that with the effect of epigenetic and environmental changes and modifier genes, the NF1: c.5392C>T mutation did not cause a severe NF1 phenotype in this family. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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