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

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.

Identification of NF1 Frameshift Variants in Two Chinese Families With Neurofibromatosis Type 1 and Early-Onset Hypertension

“…Kang et al ( 48 ) studied patients with different mutation types and found that patients with truncating/splicing mutations and large deletions tended to present with a more severe phenotype and earlier onset age than those with missense types. Recently, Scala et al ( 49 ) identified that frameshift variants and whole gene deletion were correlated with skeletal abnormalities, whereas neurofibromas were negatively associated with missense variants. Moreover, they found that the presence of structural brain alterations was associated with c.3721C>T variant, whereas Lisch nodules and endocrinological disorders were more common observed in NF-1 patients with c.6855C>A variant.…”

Neurofibromatosis: analysis of clinical cases and new diagnostic criteria

“…Как правило, у пациентов с протяженными делециями чаще наблюдаются фациальная дисплазия, задержка психоречевого и психомоторного развития, плексиформные нейрофибромы [25].…”

Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1

“…This process benefits from both NF1 families and NF1-related animal models. In a recent large cohort study with 365 NF1 subjects included, whole-gene deletions and frameshift variants are found correlated with skeletal abnormalities, including scoliosis and sphenoid bone dysplasia ( 88 ). From another 10 unrelated Chinese families who affected NF1 with main complaint of osseous lesions, five novel pathogenic variants including one missense variant and four frameshift variants are detected ( 89 ).…”