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Two Novel NF1 Pathogenic Variants Causing the Creation of a New Splice Site in Patients With Neurofibromatosis Type I.

ABSTRACT: Neurofibromatosis type I (NF1) is one of the most common autosomal dominant disorders, since the estimated incidence is one in 3,500 births. In this study, we present bioinformatical and functional characterization of two novel splicing NF1 variants, detected in NF1 patients. Patient 1, carrying NF1:c.122A>T, which introduces a new exonic 5' donor splice site, was diagnosed with hormone-positive, Her-2-negative breast cancer at the age of 47. She had an atypical presentation of NF1, with few café-au-lait spots and no Lisch nodules. Patient developed a hemothorax due to subclavian artery rupture, which has previously been described as an extremely rare complication of NF1. Patient 2, carrying NF1:c.7395-17T>G that creates a new intronic 3' acceptor splice site, had quite a typical clinical presentation of NF1: formations on her tongue in the region of her left metacarpal bones and on her left foot, plexiform neurofibroma in her pelvis, several café-au-lait spots, and axillary freckling. She was also diagnosed with cognitive impairment. In the report, we are presenting two novel variants which were successfully classified based on NGS and mRNA analysis. Based on results of mRNA analysis, both variants were classified as likely pathogenic according to ACMG guidelines applying evidence categories PS3, PM2, PP3, and PP1 supporting. By characterizing those two novel NF1 splicing variants, we have confirmed the neurofibromatosis type I phenotype in the two probands.

SUBMITTER: Setrajcic Dragos V

PROVIDER: S-EPMC6714493 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Two Novel NF1 Pathogenic Variants Causing the Creation of a New Splice Site in Patients With Neurofibromatosis Type I.

Setrajcic Dragos Vita V Blatnik Ana A Klancar Gasper G Stegel Vida V Krajc Mateja M Blatnik Olga O Novakovic Srdjan S

Frontiers in genetics 20190822

Neurofibromatosis type I (NF1) is one of the most common autosomal dominant disorders, since the estimated incidence is one in 3,500 births. In this study, we present bioinformatical and functional characterization of two novel splicing NF1 variants, detected in NF1 patients. Patient 1, carrying NF1:c.122A>T, which introduces a new exonic 5' donor splice site, was diagnosed with hormone-positive, Her-2-negative breast cancer at the age of 47. She had an atypical presentation of NF1 ...[more]

PMID: 31507634

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Project description: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.

Dataset Information

Two Novel NF1 Pathogenic Variants Causing the Creation of a New Splice Site in Patients With Neurofibromatosis Type I.

Publications

Two Novel <i>NF1</i> Pathogenic Variants Causing the Creation of a New Splice Site in Patients With Neurofibromatosis Type I.

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