Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

• Published in: Cancers Vol. 13; no. 8; p. 1879
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14-04-2021; MDPI
• Subjects: Brain cancer; Cohort analysis; Copy number; Diagnosis; Family medical history; Females; Genetic disorders; Genetic diversity; Genetic screening; Genotype & phenotype; Genotypes; Learning disabilities; Males; Medical imaging; Nervous system; Neurofibromatosis; Neurofibromin 1; Neurological disorders; Next-generation sequencing; Patients; Pediatrics; Phenotypes; Recklinghausen's disease; Statistical analysis; Statistics; Tumor suppressor genes; Tumors; neurofibromatosis type I; MLPA; genotype–phenotype correlations; NF1; cDNA sequencing; brain tumor; stop-gain; NGS; splicing
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13081879

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in
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 (
= 0.005). Skeletal abnormalities were associated with whole gene deletions (
= 0.05) and frameshift variants (
= 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (
= 0.031), whereas Lisch nodules (
= 0.05) and endocrinological disorders (
= 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.