Clinical Characteristics and Mutation Spectrum of Neurofibromatosis Type 1 in 27 Turkish Families

Abstract

Background Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder that results in a predisposition to the growth of multiple tumors in the central nervous system, the peripheral nervous system, and the skin. The clinical manifestations of neurofibromatosis are associated with loss of neurofibromin expression which causes the upregulation of the RAS pathway. Although neurofibromatosis type 1 can be diagnosed based on the National Institutes of Health criteria, sometimes the diagnosis is difficult, in cases where the characteristic features do not develop. Moreover, other RAS-related disorders may present with significantly overlapping clinical features. Aims To determine the clinical and molecular genetic characteristics of Turkish patients with neurofibromatosis type 1. Study design Cross-sectional study. Methods For the genetic analysis of 27 Turkish families clinically diagnosed with NF1 between 1990 and 2019, we used a multi-step process consisting of next-generation sequencing, multiplex ligation-dependent probe amplification, and array-comparative genomic hybridization. Results In this study, we identified 11 novel and 11 previously reported single-nucleotide variants in 22 families. Whole gene deletions were detected by multiplex ligation-dependent probe amplification analysis in 3 families. Of those, array comparative genomic hybridization analysis defined a 17q11.2 deletion in 4 patients from 2 families and 1.2-Mb involving 1 unrelated patient. All patients with a deletion had facial dysmorphism, suggesting a peculiar phenotype in this group. We could not find any pathogenic variant in the 2 families that met the National Institutes of Health criteria. Conclusion The novel pathogenic variants identified in this study broaden the spectrum of pathogenic variants in NF1 and provide better clinical characterization of NF1. RNA-seq experiments are recommended in patients who meet the National Institutes of Health diagnostic criteria for NF but have not identified any variants in next-generation sequencing, multiplex ligation-dependent probe amplification, or array-comparative genomic hybridization analysis.

Genetic evaluation of 50 Turkish patients with neurofibromatosis type 1: 2 years experience of a single center

“…The variant detection rate in our study group was 56% (28/50) and it was 71.4% (25/35) within the index patients. This rate is similar to recent case series from Turkey, which reported diagnostic rates of 66.7%, 72.4%, 80.7% and 81.4% excluding cases with large deletions (Ece Solmaz et al, 2021; Güneş et al, 2021; Sharifi et al, 2021; Ulusal et al, 2017). Based on family history, 12 of the 25 (48%) patients with detected variants were the first affected patients in their respective families.…”