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Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study
SIMPLE SUMMARY: Neurofibromatosis type 1 (NF1) is a complex disorder characterized by a multisystem involvement and cancer predisposition. It is caused by genetic variants in NF1, a large tumor suppressor gene encoding a cytoplasmatic protein (neurofibromin) with a regulatory role in essential cellu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070780/ https://www.ncbi.nlm.nih.gov/pubmed/33919865 http://dx.doi.org/10.3390/cancers13081879 |
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author | Scala, Marcello Schiavetti, Irene Madia, Francesca Chelleri, Cristina Piccolo, Gianluca Accogli, Andrea Riva, Antonella Salpietro, Vincenzo Bocciardi, Renata Morcaldi, Guido Di Duca, Marco Caroli, Francesco Verrico, Antonio Milanaccio, Claudia Viglizzo, Gianmaria Traverso, Monica Baldassari, Simona Scudieri, Paolo Iacomino, Michele Piatelli, Gianluca Minetti, Carlo Striano, Pasquale Garrè, Maria Luisa De Marco, Patrizia Diana, Maria Cristina Capra, Valeria Pavanello, Marco Zara, Federico |
author_facet | Scala, Marcello Schiavetti, Irene Madia, Francesca Chelleri, Cristina Piccolo, Gianluca Accogli, Andrea Riva, Antonella Salpietro, Vincenzo Bocciardi, Renata Morcaldi, Guido Di Duca, Marco Caroli, Francesco Verrico, Antonio Milanaccio, Claudia Viglizzo, Gianmaria Traverso, Monica Baldassari, Simona Scudieri, Paolo Iacomino, Michele Piatelli, Gianluca Minetti, Carlo Striano, Pasquale Garrè, Maria Luisa De Marco, Patrizia Diana, Maria Cristina Capra, Valeria Pavanello, Marco Zara, Federico |
author_sort | Scala, Marcello |
collection | PubMed |
description | SIMPLE SUMMARY: Neurofibromatosis type 1 (NF1) is a complex disorder characterized by a multisystem involvement and cancer predisposition. It is caused by genetic variants in NF1, a large tumor suppressor gene encoding a cytoplasmatic protein (neurofibromin) with a regulatory role in essential cellular processes. Genotype–phenotype correlations in NF1 patients are so far elusive. We retrospectively reviewed clinical, radiological, and genetic data of 583 individuals with at least 1 National Institutes of Health (NIH) criterion for NF1 diagnosis, including 365 subjects fulfilling criteria for the diagnosis. Novel genotype–phenotype correlations were identified through uni- and multivariate statistical analysis. Missense variants negatively correlated with neurofibromas. Skeletal abnormalities were associated with frameshift variants and whole gene deletions. The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations, whereas the c.6855C>A; p.(Y2285*) variant was associated with a higher prevalence of Lisch nodules and endocrinological disorders. These novel NF1 genotype–phenotype correlations may have a relevant role in the implementation of patients’ care. ABSTRACT: Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management. |
format | Online Article Text |
id | pubmed-8070780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80707802021-04-26 Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study Scala, Marcello Schiavetti, Irene Madia, Francesca Chelleri, Cristina Piccolo, Gianluca Accogli, Andrea Riva, Antonella Salpietro, Vincenzo Bocciardi, Renata Morcaldi, Guido Di Duca, Marco Caroli, Francesco Verrico, Antonio Milanaccio, Claudia Viglizzo, Gianmaria Traverso, Monica Baldassari, Simona Scudieri, Paolo Iacomino, Michele Piatelli, Gianluca Minetti, Carlo Striano, Pasquale Garrè, Maria Luisa De Marco, Patrizia Diana, Maria Cristina Capra, Valeria Pavanello, Marco Zara, Federico Cancers (Basel) Article SIMPLE SUMMARY: Neurofibromatosis type 1 (NF1) is a complex disorder characterized by a multisystem involvement and cancer predisposition. It is caused by genetic variants in NF1, a large tumor suppressor gene encoding a cytoplasmatic protein (neurofibromin) with a regulatory role in essential cellular processes. Genotype–phenotype correlations in NF1 patients are so far elusive. We retrospectively reviewed clinical, radiological, and genetic data of 583 individuals with at least 1 National Institutes of Health (NIH) criterion for NF1 diagnosis, including 365 subjects fulfilling criteria for the diagnosis. Novel genotype–phenotype correlations were identified through uni- and multivariate statistical analysis. Missense variants negatively correlated with neurofibromas. Skeletal abnormalities were associated with frameshift variants and whole gene deletions. The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations, whereas the c.6855C>A; p.(Y2285*) variant was associated with a higher prevalence of Lisch nodules and endocrinological disorders. These novel NF1 genotype–phenotype correlations may have a relevant role in the implementation of patients’ care. ABSTRACT: Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management. MDPI 2021-04-14 /pmc/articles/PMC8070780/ /pubmed/33919865 http://dx.doi.org/10.3390/cancers13081879 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Scala, Marcello Schiavetti, Irene Madia, Francesca Chelleri, Cristina Piccolo, Gianluca Accogli, Andrea Riva, Antonella Salpietro, Vincenzo Bocciardi, Renata Morcaldi, Guido Di Duca, Marco Caroli, Francesco Verrico, Antonio Milanaccio, Claudia Viglizzo, Gianmaria Traverso, Monica Baldassari, Simona Scudieri, Paolo Iacomino, Michele Piatelli, Gianluca Minetti, Carlo Striano, Pasquale Garrè, Maria Luisa De Marco, Patrizia Diana, Maria Cristina Capra, Valeria Pavanello, Marco Zara, Federico Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study |
title | Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study |
title_full | Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study |
title_fullStr | Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study |
title_full_unstemmed | Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study |
title_short | Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study |
title_sort | genotype-phenotype correlations in neurofibromatosis type 1: a single-center cohort study |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070780/ https://www.ncbi.nlm.nih.gov/pubmed/33919865 http://dx.doi.org/10.3390/cancers13081879 |
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