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
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genoa, Italy.
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, University of Genoa, 16147 Genoa, Italy.
Cancers (Basel). 2021 Apr 14;13(8):1879. 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.
1型神经纤维瘤病（NF1）是一种由致病变异引起的具有多种表现形式的遗传性疾病，其特征为表型呈现异质性。最近出现了相关的基因型-表型相关性，但仅有少数相关研究。我们回顾性分析了583名符合至少1项美国国立卫生研究院（NIH）NF1诊断标准的个体的临床、影像学和基因数据。其中，365名受试者符合≥2项NIH标准，包括235名儿科患者。通过基于cDNA的测序、下一代测序（NGS）和多重连接依赖探针扩增（MLPA）进行基因检测。采用单变量和多变量统计分析来研究基因型-表型相关性。在符合≥2项NIH标准的患者中，在267/365（73.2%）和20/365（5.5%）的病例中检测到致病单核苷酸变异（SNV）和拷贝数变异（CNV）。错义变异与神经纤维瘤呈负相关（P = 0.005）。骨骼异常与全基因缺失（P = 0.05）和移码变异（P = 0.006）相关。c.3721C>T；p.(R1241*)变异与脑部结构改变呈正相关（P = 0.031），而Lisch结节（P = 0.05）和内分泌紊乱（P = 0.043）与c.6855C>A；p.(Y2285*)变异相关。我们确定了新的NF1基因型-表型相关性，并概述了已知关联情况，支持它们在患者管理实施中的潜在相关性。
