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https://hdl.handle.net/2440/113931
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Type: | Journal article |
Title: | Genotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848 |
Author: | Koczkowska, M. Chen, Y. Callens, T. Gomes, A. Sharp, A. Johnson, S. Hsiao, M. Chen, Z. Balasubramanian, M. Barnett, C. Becker, T. Ben-Shachar, S. Bertola, D. Blakeley, J. Burkitt-Wright, E. Callaway, A. Crenshaw, M. Cunha, K. Cunningham, M. D'Agostino, M. et al. |
Citation: | American Journal of Human Genetics, 2018; 102(1):69-87 |
Publisher: | Cell Press |
Issue Date: | 2018 |
ISSN: | 0002-9297 1537-6605 |
Statement of Responsibility: | Magdalena Koczkowska, Yunjia Chen, Tom Callens, Alicia Gomes … Christopher P. Barnett … Yoon-Sim Yap … et al. |
Abstract: | Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals. |
Keywords: | CSRD MPNST NF1 codons 844–848 genotype-phenotype correlation missense mutation neurofibromatosis type 1 plexiform neurofibroma spinal NF |
Rights: | © 2017 The Authors. This is an open access article under the CC BY -NC-ND license (http ://creativecommons.org/licenses/by-nc-nd/4 .0/) |
DOI: | 10.1016/j.ajhg.2017.12.001 |
Published version: | http://dx.doi.org/10.1016/j.ajhg.2017.12.001 |
Appears in Collections: | Agriculture, Food and Wine publications Aurora harvest 3 |
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hdl_113931.pdf | Published version | 610.77 kB | Adobe PDF | View/Open |
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