Current studentsExisting staffContact us
 

Genotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848

Simple item page
dc.contributor.authorKoczkowska, M.
dc.contributor.authorChen, Y.
dc.contributor.authorCallens, T.
dc.contributor.authorGomes, A.
dc.contributor.authorSharp, A.
dc.contributor.authorJohnson, S.
dc.contributor.authorHsiao, M.
dc.contributor.authorChen, Z.
dc.contributor.authorBalasubramanian, M.
dc.contributor.authorBarnett, C.
dc.contributor.authorBecker, T.
dc.contributor.authorBen-Shachar, S.
dc.contributor.authorBertola, D.
dc.contributor.authorBlakeley, J.
dc.contributor.authorBurkitt-Wright, E.
dc.contributor.authorCallaway, A.
dc.contributor.authorCrenshaw, M.
dc.contributor.authorCunha, K.
dc.contributor.authorCunningham, M.
dc.contributor.authorD'Agostino, M.
dc.contributor.authoret al.
dc.date.issued2018
dc.description.abstractNeurofibromatosis 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.statementofresponsibilityMagdalena Koczkowska, Yunjia Chen, Tom Callens, Alicia Gomes … Christopher P. Barnett … Yoon-Sim Yap … et al.
dc.identifier.citationAmerican Journal of Human Genetics, 2018; 102(1):69-87
dc.identifier.doi10.1016/j.ajhg.2017.12.001
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.orcidBarnett, C. [0000-0003-1717-3824]
dc.identifier.urihttp://hdl.handle.net/2440/113931
dc.language.isoen
dc.publisherCell 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.urihttps://doi.org/10.1016/j.ajhg.2017.12.001
dc.subjectCSRD
dc.subjectMPNST
dc.subjectNF1
dc.subjectcodons 844–848
dc.subjectgenotype-phenotype correlation
dc.subjectmissense mutation
dc.subjectneurofibromatosis type 1
dc.subjectplexiform neurofibroma
dc.subjectspinal NF
dc.titleGenotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848
dc.typeJournal article
pubs.publication-statusPublished

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
hdl_113931.pdf
Size:
610.77 KB
Format:
Adobe Portable Document Format
Description:
Published version
Download

Collections

Agriculture, Food and Wine publications