Neurofibromatosis Type 1 and Type2 (NF1 and NF2): Molecular Genetic Profiles of the Patients

INTRODUCTION: Neurofibromatosis type I and type 2 (NF1 and NF2) are two rare autosomal dominant neurocutaneous genetic disorders that are diagnosed based on clinical diagnostic criteria of the National Institutes of Health Consensus. Due to increased malignancy risks and age-related penetrance, NGS-based diagnosis methods should be used for early diagnosis. However, molecular diagnosis of the NF1 and NF2 genes are challenging owing to the large size of genes, and the lack of mutation hotspots. In this study, we present 67 patients between 2016-2019 who were investigated for NF1 and NF2 genes with the next generation sequencing (NGS). We aimed to show the effectiveness of NGS-based molecular genetic diagnoses and contribute to establishing the variant spectrum in the Turkish population.
METHODS: Patients who met the diagnostic criteria were included in this study. After DNA extraction from peripheric blood samples, an NGS-based panel that includes both NF1 and NF2 genes was performed. Results were evaluated using ACMG 2015 criteria and in silico bioinformatics tools.
RESULTS: 39 of 67 total patients revealed various variants (39/67, ~%58). The variant distribution was as follows; 15 frameshift, 8 nonsense, 7 missense, 6 splice sites, and three insertion/deletion. Novel variants ratio was 23/39 (22 NF1, 1 NF2, ~%59). The classification according to clinical significance was as follows: 23 pathogenic, 14 likely pathogenic, and one VUS according to ACMG 2015 criteria.
DISCUSSION AND CONCLUSION: Our results suggested that a genetic screening using an NGS panel is more useful and helpful to provide early diagnosis and genetic counseling and have a positive impact on patient follow-up.

Nörofibromatozis Tip 1 ve Tip2 (NF1 ve NF2): Hastalarýn Moleküler Genetik Profilleri

GÝRÝÞ ve AMAÇ: Nörofibromatozis tip I ve tip 2 (NF1 ve NF2), Ulusal Saðlýk Konsensüsü Enstitüleri'nin klinik taný kriterlerine göre teþhis edilen iki nadir otozomal dominant nörokutanöz genetik hastalýktýr. Artan malignite riskleri ve yaþa baðlý penetrans nedeniyle erken taný için NGS temelli taný yöntemleri kullanýlmalýdýr. Bununla birlikte, NF1 ve NF2 genlerinin moleküler teþhisi, genlerin büyük boyutu ve mutasyon noktalarýnýn olmamasý nedeniyle zordur. Bu çalýþmada 2016-2019 yýllarý arasýnda yeni nesil dizileme (NGS) ile NF1 ve NF2 genleri araþtýrýlan 67 hasta sunuldu. NGS temelli moleküler genetik tanýlarýn etkinliðini göstermeyi ve Türk popülasyonunda varyant spektrumunun oluþturulmasýna katkýda bulunmayý amaçladýk.
YÖNTEM ve GEREÇLER: Taný kriterlerini karþýlayan hastalar dahil edildi.
Periferik kan örneklerinden DNA ekstraksiyonundan sonra, hem NF1 hem de NF2 genlerini içeren NGS tabanlý bir panel gerçekleþtirildi. Sonuçlar ACMG 2015 kriterleri ve in silico biyoinformatik araçlarý kullanýlarak deðerlendirildi.

BULGULAR: Toplam 67 hastanýn 39'unda çeþitli varyantlar saptandý (39/67, ~%58). Varyant daðýlýmý þu þekildeydi; 15 çerçeve kaymasý, 8 anlamsýz, 7 yanlýþ anlamlý, 6 splays bölge ve üç insersiyon/delesyon. Yeni varyant oraný 23/39 (22 NF1, 1 NF2, ~%59) idi. Klinik öneme göre sýnýflandýrma þu þekildeydi: ACMG 2015 kriterlerine göre 23 patojenik, 14 olasý patojenik ve bir VUS
TARTIÞMA ve SONUÇ: Sonuçlarýmýz, bir NGS paneli kullanýlarak yapýlan genetik taramanýn, erken taný ve genetik danýþmanlýk saðlamak için daha yararlý ve yararlý olduðunu ve hasta takibini olumlu yönde etkilediðini göstermiþtir.