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

INTRODUCTION

Neurofibromatosis Type I (NF1; MIM #162200), first described by von Recklinghausen in 1882, is a multi systemic autosomal dominant neurocutaneous disorder predisposing patients to have benign and/or malignant lesions predominantly of the skin, nervous system and bone. It affects about 1/3000 of the population as being one of the most common autosomal dominant disorders [1-3]. Common clinical manifestations include hyperpigmentation lesions of the skin called café-au-lait macules or spots (CAM, CAS), dermal or plexiform neurofibromas, axillary and inguinal freckling, iris hamartomas in the eye called Lisch nodules, optic pathway gliomas, sphenoid or long bone dysplasia and pseudoarthrosis. Some clinical manifestations are age dependent [1,4-7]. Current clinical diagnosis of NF1 is based on the criteria approved by the National Institutes of Health (NIH), Bethesda, MD, USA, consensus in 1988 [8]. Loss of function mutations or deletions of the NF1 (Neurofibromin 1; MIM #613113) gene located at 17q11.2 encoding a ras-GTPase-activating protein called neuro- fibromin is responsible for NF1 disease [1]. More than 2000 pathogenic variations listed in the Human Gene Mutation Database (HGMD) including splice site changes, nonsense and missense mutations, deletions, insertions, frameshifts and complex rearrangements [9]. About half of the pathogenic variations found in patients are de novo occurrences. Involvement of various pathogenic variants without a clear hotspot, the large size of the gene and presence of pseudogenes makes it difficult to analyze. Genetic diagnosis generally requires a multi methodological approach [1]. With the advances in next generation sequencing (NGS), it became easier to analyze the whole coding exons of large genes simultaneously in a short time. On the other hand, multiplex ligation-dependent probe amplification (MLPA) is a practical way of defining gene deletions and duplications. These techniques together have a powerful tool for genetic diagnosis of NF1 [3,10,11]. Determining the pathogenic variant can assist in diagnosing the patients who have an uncertain diagnosis of NF1 [12,13]. Advances in preimplantation genetic diagnosis (PGD) and prenatal genetic testing might be helpful for the individuals who have a pathogenic variant causing NF1 [14]. In this study, we aimed to present the NF1 gene alterations determined in genomic DNA samples of Turkish NF1 patients using both NGS and MLPA between March 2014 and March 2016.

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