Balkan Journal of Medical Genetics

CASE REPORT FOR TWO SIBLINGS CARRYING NEUROFIBROMATOSIS TYPE 1 WITH A RARE NF1: c.5392C>T MUTATION
Sayın Kocakap DB1,*, Gündüz Ö2 , Özer L3 , Durak M
*Corresponding Author: : Associate Professor Derya B. Sayın Kocakap, Kırıkkale Üniversitesi Tıp FakültesiTıbbi GenetikAD,AnkaraYolu 7.km, 71450, Kırıkkale,Turkey.Tel.: +90-318-357-3300/5784. Fax: +90-318-225-2819. E-mail: dsayin@yahoo.com
page: 0

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 variantsin 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. Neurofibromatosistype 1 has great clinical variability even between affected individuals of the same family with the same mutation. Our represented cases of siblings also show inter-individual variation; they have differentfeatures ofskin 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.

Number 27 VOL. 27 (2), 2024	Number 27 VOL. 27 (1), 2024
Number 26 Number 26 VOL. 26(2), 2023 All in one	Number 26 VOL. 26(2), 2023
Number 26 VOL. 26, 2023 Supplement	Number 26 VOL. 26(1), 2023
Number 25 VOL. 25(2), 2022	Number 25 VOL. 25 (1), 2022
Number 24 VOL. 24(2), 2021	Number 24 VOL. 24(1), 2021
Number 23 VOL. 23(2), 2020	Number 22 VOL. 22(2), 2019
Number 22 VOL. 22(1), 2019	Number 22 VOL. 22, 2019 Supplement
Number 21 VOL. 21(2), 2018	Number 21 VOL. 21 (1), 2018
Number 21 VOL. 21, 2018 Supplement	Number 20 VOL. 20 (2), 2017
Number 20 VOL. 20 (1), 2017	Number 19 VOL. 19 (2), 2016
Number 19 VOL. 19 (1), 2016	Number 18 VOL. 18 (2), 2015
Number 18 VOL. 18 (1), 2015	Number 17 VOL. 17 (2), 2014
Number 17 VOL. 17 (1), 2014	Number 16 VOL. 16 (2), 2013
Number 16 VOL. 16 (1), 2013	Number 15 VOL. 15 (2), 2012
Number 15 VOL. 15, 2012 Supplement	Number 15 Vol. 15 (1), 2012
Number 14 14 - Vol. 14 (2), 2011	Number 14 The 9th Balkan Congress of Medical Genetics
Number 14 14 - Vol. 14 (1), 2011	Number 13 Vol. 13 (2), 2010
Number 13 Vol.13 (1), 2010	Number 12 Vol.12 (2), 2009
Number 12 Vol.12 (1), 2009	Number 11 Vol.11 (2),2008
Number 11 Vol.11 (1),2008	Number 10 Vol.10 (2), 2007
Number 10 10 (1),2007	Number 9 1&2, 2006
Number 9 3&4, 2006	Number 8 1&2, 2005
Number 8 3&4, 2004	Number 7 1&2, 2004
Number 6 3&4, 2003	Number 6 1&2, 2003
Number 5 3&4, 2002	Number 5 1&2, 2002
Number 4 Vol.3 (4), 2000	Number 4 Vol.2 (4), 1999
Number 4 Vol.1 (4), 1998	Number 4 3&4, 2001
Number 4 1&2, 2001	Number 3 Vol.3 (3), 2000
Number 3 Vol.2 (3), 1999	Number 3 Vol.1 (3), 1998
Number 2 Vol.3(2), 2000	Number 2 Vol.1 (2), 1998
Number 2 Vol.2 (2), 1999	Number 1 Vol.3 (1), 2000
Number 1 Vol.2 (1), 1999	Number 1 Vol.1 (1), 1998

About the journal ::: Editorial ::: Subscription ::: Information for authors ::: Contact