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Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic diseases. It is caused by mutations in the NF1 gene encoding for the large protein, neurofibromin. Genetic testing of NF1 is cumbersome because 50% of cases are sporadic, and there are no mutation hot spots. In addit...

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Autores principales: Stella, Alessandro, Lastella, Patrizia, Loconte, Daria Carmela, Bukvic, Nenad, Varvara, Dora, Patruno, Margherita, Bagnulo, Rosanna, Lovaglio, Rosaura, Bartolomeo, Nicola, Serio, Gabriella, Resta, Nicoletta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924558/
https://www.ncbi.nlm.nih.gov/pubmed/29673180
http://dx.doi.org/10.3390/genes9040216
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author Stella, Alessandro
Lastella, Patrizia
Loconte, Daria Carmela
Bukvic, Nenad
Varvara, Dora
Patruno, Margherita
Bagnulo, Rosanna
Lovaglio, Rosaura
Bartolomeo, Nicola
Serio, Gabriella
Resta, Nicoletta
author_facet Stella, Alessandro
Lastella, Patrizia
Loconte, Daria Carmela
Bukvic, Nenad
Varvara, Dora
Patruno, Margherita
Bagnulo, Rosanna
Lovaglio, Rosaura
Bartolomeo, Nicola
Serio, Gabriella
Resta, Nicoletta
author_sort Stella, Alessandro
collection PubMed
description Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic diseases. It is caused by mutations in the NF1 gene encoding for the large protein, neurofibromin. Genetic testing of NF1 is cumbersome because 50% of cases are sporadic, and there are no mutation hot spots. In addition, the most recognizable NF1 clinical features—café-au-lait (CALs) spots and axillary and/or inguinal freckling—appear early in childhood but are rather non-specific. Thus, the identification of causative variants is extremely important for early diagnosis, especially in paediatric patients. Here, we aimed to identify the underlying genetic defects in 72 index patients referred to our centre for NF1. Causative mutations were identified in 58 subjects, with 29 being novel changes. We evaluated missense and non-canonical splicing mutations with both protein and splicing prediction algorithms. The ratio of splicing mutations detected was higher than that reported in recent patients’ series and in the Human Gene Mutation Database (HGMD). After applying in silico predictive tools to 41 previously reported missense variants, we demonstrated that 46.3% of these putatively missense mutations were forecasted to alter splicing instead. Our data suggest that mutations affecting splicing can be frequently underscored if not analysed in depth. We confirm that hamartomas can be useful for diagnosing NF1 in children. Lisch nodules and cutaneous neurofibromas were more frequent in patients with frameshifting mutations. In conclusion, we demonstrated that comprehensive in silico analysis can be a highly specific method for predicting the nature of NF1 mutations and may help in assuring proper patient care.
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spelling pubmed-59245582018-05-03 Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1 Stella, Alessandro Lastella, Patrizia Loconte, Daria Carmela Bukvic, Nenad Varvara, Dora Patruno, Margherita Bagnulo, Rosanna Lovaglio, Rosaura Bartolomeo, Nicola Serio, Gabriella Resta, Nicoletta Genes (Basel) Article Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic diseases. It is caused by mutations in the NF1 gene encoding for the large protein, neurofibromin. Genetic testing of NF1 is cumbersome because 50% of cases are sporadic, and there are no mutation hot spots. In addition, the most recognizable NF1 clinical features—café-au-lait (CALs) spots and axillary and/or inguinal freckling—appear early in childhood but are rather non-specific. Thus, the identification of causative variants is extremely important for early diagnosis, especially in paediatric patients. Here, we aimed to identify the underlying genetic defects in 72 index patients referred to our centre for NF1. Causative mutations were identified in 58 subjects, with 29 being novel changes. We evaluated missense and non-canonical splicing mutations with both protein and splicing prediction algorithms. The ratio of splicing mutations detected was higher than that reported in recent patients’ series and in the Human Gene Mutation Database (HGMD). After applying in silico predictive tools to 41 previously reported missense variants, we demonstrated that 46.3% of these putatively missense mutations were forecasted to alter splicing instead. Our data suggest that mutations affecting splicing can be frequently underscored if not analysed in depth. We confirm that hamartomas can be useful for diagnosing NF1 in children. Lisch nodules and cutaneous neurofibromas were more frequent in patients with frameshifting mutations. In conclusion, we demonstrated that comprehensive in silico analysis can be a highly specific method for predicting the nature of NF1 mutations and may help in assuring proper patient care. MDPI 2018-04-17 /pmc/articles/PMC5924558/ /pubmed/29673180 http://dx.doi.org/10.3390/genes9040216 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Stella, Alessandro
Lastella, Patrizia
Loconte, Daria Carmela
Bukvic, Nenad
Varvara, Dora
Patruno, Margherita
Bagnulo, Rosanna
Lovaglio, Rosaura
Bartolomeo, Nicola
Serio, Gabriella
Resta, Nicoletta
Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1
title Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1
title_full Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1
title_fullStr Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1
title_full_unstemmed Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1
title_short Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1
title_sort accurate classification of nf1 gene variants in 84 italian patients with neurofibromatosis type 1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924558/
https://www.ncbi.nlm.nih.gov/pubmed/29673180
http://dx.doi.org/10.3390/genes9040216
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