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

Abstract

Background: Neurofibromatosis type 1 (NF-1) is a common autosomal dominant disorder caused by mutations in the NF1 gene. It is characterized by multiple café-au-lait macules, cutaneous neurofibromas, optic glioma, Lisch nodules, and axillary and inguinal freckling. The aim of this study was to investigate NF1 mutations in two Chinese families with NF-1 who presented with early-onset hypertension, and to determine the prevalence of hypertension associated with NF-1 to better understand this complication.Methods: Whole-exome sequencing was performed for the probands with NF-1 from two unrelated families. Possible pathogenic mutation was predicted by bioinformatic tools. Sanger sequencing was used to confirm candidate variants in all available individuals for familial co-segregation analysis. We also performed a systematic literature review of studies that reported the prevalence of hypertension in patients with NF-1.Results: In family 1, a recurrent mutation c.6789_6792delTTAC in NF1 was identified in the proband but in no other family members, indicating that this is a de novo mutation. In family 2, a novel mutation c.6934_6936delGCAinsTGCT in NF1 was detected in the proband and two other family members, which co-segregated with the disease phenotype within the family. Both mutations were predicted to be pathogenic by bioinformatic analysis. We found hypertension was a relatively common complication of NF-1, with a prevalence range of 6.1–23.4%. Ambulatory blood pressure monitoring is a stable method for detecting initial alterations of the blood pressure pattern, particularly for pre-hypertension.Conclusions: We identified one recurrent (c.6789_6792delTTAC) and one novel frame-shift mutation (c.6934_6936delGCAinsTGCT) in two unrelated families with NF-1 using whole-exome sequencing. In consideration of phenotypic heterogeneity in NF-1, genetic testing is a robust tool which helps early and accurate diagnosis. Because hypertension is not a rare complication of NF-1, routine screening for hypertension in patients with NF-1, especially children and adolescents, is important to avoid serious cardiovascular events.

Identifying a novel frameshift pathogenic variant in a Chinese family with neurofibromatosis type 1 and review of literature

“…The studies included case analysis and multiple case analysis, mainly for NF1 gene mutation, with various types of mutation, including point mutation, frameshift mutation, splice site mutation, exon mutation, chimeric mutation and de novo mutation. All reported autosomal dominant inheritance [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . DISCUSSION Neurofibromatosis type 1 is a multisystem genetic disease with more than 3000 NF1-related pathogenic variants reported, but pathogenic variants in exon 33 are extremely underrepresented.…”

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing <i>NF1</i> Mutation

“…Cutaneous presentations such as dermal neurofibromas and pigmentation are the most common features of NF-1 with early penetrance, whereas cardiovascular complications are non-neoplastic and easily overlooked but have significant manifestations that can potentially lead to catastrophic outcomes and reduced average life expectancy [21][22][23]. Hypertension is frequently detected in patients with NF-1 and is associated with essential hypertension, renal or aortic vasculopathy, and pheochromocytoma/paraganglioma [24]. Renal vasculopathy is the primary cause of refractory renovascular hypertension in patients with NF-1, accounting for approximately 1% of patients [25,26].…”