Balkan Journal of Medical Genetics

GENETIC ANALYSES OF THE NF1 GENE IN TURKISH NEUROFIBROMATOSIS TYPE I PATIENTS AND DEFINITION OF THREE NOVEL VARIANTS
Ulusal SD1,*, Gürkan H1, Atlı E1, Özal SA2, Çiftdemir M3, Tozkır H1, Karal Y4, Güçlü H2, Eker D1, Görker I5
*Corresponding Author: Dr. Selma D. Ulusal, Department of Medical Genetics, Trakya University Faculty of Medicine, D100, Edirne, Turkey. Tel: +90-284-235-7642/2330. Fax: +90-284-235-7652. E-mail: selmaulusal@trakya.edu.tr
page: 13

DISCUSSION

A lot of different pathogenic variations have been reported in the NF1 gene [18-28] but this is the first report to include results of NGS and MLPA methods for diagnosis of NF1 in Turkish patients. We defined NF1 gene pathogenic variants in 13 out of 17 (76.0%) patients, who met the NIH diagnostic criteria. In a study performed in the Japanese population including 86 NF1 patients [11], the mutation detection rate of the NGS method has been reported to be 92.1%. In another study performed on 279 NF1 patients, researchers suggested the mutation detection rate of NGS was 88.0% (3). The different mutation frequencies in the studies may be because of the differences between the library preparation method and specifications of the studied patient group. In our study, eight out of 24 patients (33.33%) had isolated cafe-aulait spots, which may also be a manifestation of other ras pathway disorders. We did not define a pathogenic variation in four out of 17 patients who met the NIH diagnostic criteria. We used an amplicon-based capture for resequencing the coding regions and exon/intron boundaries (splice sites) of the NF1 gene. Deep intronic pathogenic variations were also reported in the patients with NF1 patients [18]. We propose that it is possible to miss some pathogenic variations located in deep intronic regions with capturing exonic and known splice sites instead of the whole gene. We report here two different truncating mutations in two unrelated patients with pseudoarthrosis. Being a relatively rare manifestation of NF1 disease, breakage because of sphenoid dysplasia is one of the most serious clinical finding restricting the life quality of children with NF1. Pathogenic variants found in this study were different for each family although there are a number of studies reporting some recurrent mutation hotspots for the NF1 gene [29,30]. Terzi et al. [31] suggested screening the entire coding exons of the NF1 gene for genetic analysis as a result of their study reporting a novel and two known NF1 gene mutations in a cohort of 100 Turkish NF1 patients using a targeted resequencing method for screening recurrent mutation hotspots. They concluded that each population may have different mutation distribution patterns in the NF1 gene. Despite the differences of the sample sizes between these two studies in the Turkish population, both support the need for a comprehensive approach for the genetic analysis of NF1 patients. Some of the pathogenic variations defined in this study were in the C-terminal region, which has recently been reported to have an important role in the cellular process [32]. There was no obvious genotype-phenotype correlation in this study but small number of studied patients might be one of the reasons. Another additional factor is the age dependence of some manifestations of the disease so it is difficult to compare family members unless they are at the same age. Highly variable expressivity has been reported in a lot of studies for NF1. Genotypephenotype correlation has been reported for a few of the mutations. A well-known example is the absence of cutaneous neurofibromas in the patients with a 3 bp inframe deletion in the NF1 gene (c.2970-2972delAAT) [33], and a more severe phenotype including intellectual disability in the patients who have a NF1 microdeletion syndrome [34]. The majority of the pathogenic variations of NF1 reported in the literature are caused by a premature stop codon generation (9). Three novel pathogenic variants (3/17) defined in this study were predicted to cause premature stop codon generation either due to frameshift deletions [c.3230_3230delT, p.(Ser1078Hisfs*3); c.4802delT, p.(Leu1601Cysfs*2)] or single nucletoide [c.5630T>A, p.(Leu1877*)] variations. The NF1 mutations cause a predisposition to cancer as do other ras pathway disorders [35]. Considering the age-dependent nature of some manifestations, it would be useful to define pathogenic variations in families with NF1 for a closer follow-up. We performed segregation analysis by Sanger sequencing in this study but, although it is impossible to define germline mosaicism by performing NGS in the blood samples of parents, NGS would reveal the somatic mosaic pathogenic variations in apparently normal patients. In conclusion, we suggest that NGS and MLPA methods are practical and helpful tools for genetic diagnosis of NF1. The definition of three novel and 13 known pathogenic variants and a large gene deletion, using a combined approach including NGS and MLPA, supports the effectiveness of new technologies for rapid and accurate genetic diagnosis of NF1 in our population. 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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