Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/113931
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dc.contributor.author | Koczkowska, M. | - |
dc.contributor.author | Chen, Y. | - |
dc.contributor.author | Callens, T. | - |
dc.contributor.author | Gomes, A. | - |
dc.contributor.author | Sharp, A. | - |
dc.contributor.author | Johnson, S. | - |
dc.contributor.author | Hsiao, M. | - |
dc.contributor.author | Chen, Z. | - |
dc.contributor.author | Balasubramanian, M. | - |
dc.contributor.author | Barnett, C. | - |
dc.contributor.author | Becker, T. | - |
dc.contributor.author | Ben-Shachar, S. | - |
dc.contributor.author | Bertola, D. | - |
dc.contributor.author | Blakeley, J. | - |
dc.contributor.author | Burkitt-Wright, E. | - |
dc.contributor.author | Callaway, A. | - |
dc.contributor.author | Crenshaw, M. | - |
dc.contributor.author | Cunha, K. | - |
dc.contributor.author | Cunningham, M. | - |
dc.contributor.author | D'Agostino, M. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | American Journal of Human Genetics, 2018; 102(1):69-87 | - |
dc.identifier.issn | 0002-9297 | - |
dc.identifier.issn | 1537-6605 | - |
dc.identifier.uri | http://hdl.handle.net/2440/113931 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Magdalena Koczkowska, Yunjia Chen, Tom Callens, Alicia Gomes … Christopher P. Barnett … Yoon-Sim Yap … et al. | - |
dc.language.iso | en | - |
dc.publisher | Cell Press | - |
dc.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/) | - |
dc.source.uri | http://dx.doi.org/10.1016/j.ajhg.2017.12.001 | - |
dc.subject | CSRD | - |
dc.subject | MPNST | - |
dc.subject | NF1 | - |
dc.subject | codons 844–848 | - |
dc.subject | genotype-phenotype correlation | - |
dc.subject | missense mutation | - |
dc.subject | neurofibromatosis type 1 | - |
dc.subject | plexiform neurofibroma | - |
dc.subject | spinal NF | - |
dc.title | Genotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848 | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1016/j.ajhg.2017.12.001 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Barnett, C. [0000-0003-1717-3824] | - |
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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