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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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
Descripción
Sumario: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.