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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doaj-4d705cb779234392a264e31123b2eb6d2020-11-24T21:04:07ZengMDPI AGGenes2073-44252018-04-019421610.3390/genes9040216genes9040216Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1Alessandro Stella0Patrizia Lastella1Daria Carmela Loconte2Nenad Bukvic3Dora Varvara4Margherita Patruno5Rosanna Bagnulo6Rosaura Lovaglio7Nicola Bartolomeo8Gabriella Serio9Nicoletta Resta10Laboratorio di Genetica Medica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalyCentro di Malattie Rare, Azienda Ospedaliero-Universitario Policlinico di Bari, 70124 Bari, ItalyLaboratorio di Genetica Medica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalyLaboratorio di Genetica Medica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalyAzienda Ospedaliero-Universitario Policlinico di Bari, 70124 Bari, ItalyLaboratorio di Genetica Medica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalyLaboratorio di Genetica Medica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalyLaboratorio di Genetica Medica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalySezione di Igiene, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalySezione di Igiene, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalyLaboratorio di Genetica Medica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, ItalyNeurofibromatosis 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.http://www.mdpi.com/2073-4425/9/4/216neurofibromatosis type 1NF1 genevariant classificationin silico analysissplicing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alessandro Stella Patrizia Lastella Daria Carmela Loconte Nenad Bukvic Dora Varvara Margherita Patruno Rosanna Bagnulo Rosaura Lovaglio Nicola Bartolomeo Gabriella Serio Nicoletta Resta |
spellingShingle |
Alessandro Stella Patrizia Lastella Daria Carmela Loconte Nenad Bukvic Dora Varvara Margherita Patruno Rosanna Bagnulo Rosaura Lovaglio Nicola Bartolomeo Gabriella Serio Nicoletta Resta Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1 Genes neurofibromatosis type 1 NF1 gene variant classification in silico analysis splicing |
author_facet |
Alessandro Stella Patrizia Lastella Daria Carmela Loconte Nenad Bukvic Dora Varvara Margherita Patruno Rosanna Bagnulo Rosaura Lovaglio Nicola Bartolomeo Gabriella Serio Nicoletta Resta |
author_sort |
Alessandro Stella |
title |
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_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_sort |
accurate classification of nf1 gene variants in 84 italian patients with neurofibromatosis type 1 |
publisher |
MDPI AG |
series |
Genes |
issn |
2073-4425 |
publishDate |
2018-04-01 |
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. |
topic |
neurofibromatosis type 1 NF1 gene variant classification in silico analysis splicing |
url |
http://www.mdpi.com/2073-4425/9/4/216 |
work_keys_str_mv |
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