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Article

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

1
Laboratorio di Genetica Medica, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy
2
Centro di Malattie Rare, Azienda Ospedaliero-Universitario Policlinico di Bari, 70124 Bari, Italy
3
Azienda Ospedaliero-Universitario Policlinico di Bari, 70124 Bari, Italy
4
Sezione di Igiene, Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy
*
Author to whom correspondence should be addressed.
Genes 2018, 9(4), 216; https://doi.org/10.3390/genes9040216
Received: 22 February 2018 / Revised: 27 March 2018 / Accepted: 3 April 2018 / Published: 17 April 2018
(This article belongs to the Section Human Genomics and Genetic Diseases)
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. View Full-Text
Keywords: neurofibromatosis type 1; NF1 gene; variant classification; in silico analysis; splicing neurofibromatosis type 1; NF1 gene; variant classification; in silico analysis; splicing
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MDPI and ACS Style

Stella, A.; Lastella, P.; Loconte, D.C.; Bukvic, N.; Varvara, D.; Patruno, M.; Bagnulo, R.; Lovaglio, R.; Bartolomeo, N.; Serio, G.; Resta, N. Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1. Genes 2018, 9, 216. https://doi.org/10.3390/genes9040216

AMA Style

Stella A, Lastella P, Loconte DC, Bukvic N, Varvara D, Patruno M, Bagnulo R, Lovaglio R, Bartolomeo N, Serio G, Resta N. Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1. Genes. 2018; 9(4):216. https://doi.org/10.3390/genes9040216

Chicago/Turabian Style

Stella, Alessandro, Patrizia Lastella, Daria C. Loconte, Nenad Bukvic, Dora Varvara, Margherita Patruno, Rosanna Bagnulo, Rosaura Lovaglio, Nicola Bartolomeo, Gabriella Serio, and Nicoletta Resta. 2018. "Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1" Genes 9, no. 4: 216. https://doi.org/10.3390/genes9040216

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