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

Magdalena Koczkowska, Yunjia Chen, Tom Callens, Alicia Gomes, Angela Sharp, Sherrell Johnson, Meng-Chang Hsiao, Zhenbin Chen, Meena Balasubramanian, Christopher P Barnett, et al. (2017) AMERICAN JOURNAL OF HUMAN GENETICS. 102(1). p.69-87
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 similar to 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.
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author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
NEUROFIBROMATOSIS TYPE-I, OPTIC PATHWAY GLIOMAS, NERVE SHEATH TUMORS, SOUTH EAST WALES, NOONAN-SYNDROME, VONRECKLINGHAUSEN NEUROFIBROMATOSIS, SPINAL NEUROFIBROMATOSIS, PLEXIFORM NEUROFIBROMAS, TYPE-1 NEUROFIBROMATOSIS, NATURAL-HISTORY
journal title
AMERICAN JOURNAL OF HUMAN GENETICS
Am. J. Hum. Genet.
volume
102
issue
1
pages
69 - 87
Web of Science type
Article
Web of Science id
000419305500006
ISSN
0002-9297
DOI
10.1016/j.ajhg.2017.12.001
language
English
UGent publication?
yes
classification
A1
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8546030
handle
http://hdl.handle.net/1854/LU-8546030
date created
2018-01-24 08:49:16
date last changed
2018-02-20 15:19:26
@article{8546030,
  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 similar to 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 {\textlangle} 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.},
  author       = {Koczkowska, Magdalena and Chen, Yunjia and Callens, Tom and Gomes, Alicia and Sharp, Angela and Johnson, Sherrell and Hsiao, Meng-Chang and Chen, Zhenbin and Balasubramanian, Meena and Barnett, Christopher P and Becker, Troy A and Ben-Shachar, Shay and Bertola, Debora R and Blakeley, Jaishri O and Burkitt-Wright, Emma MM and Callaway, Alison and Crenshaw, Melissa and Cunha, Karin S and Cunningham, Mitch and D{\textquoteright}Agostino, Maria D and Dahan, Karin and De Luca, Alessandro and Destr{\'e}e, Anne and Dhamija, Radhika and Eoli, Marica and Evans, D Gareth R and Galvin-Parton, Patricia and George-Abraham, Jaya K and Gripp, Karen W and Guevara-Campos, Jose and Hanchard, Neil A and Hern{\'a}ndez-Chico, Concepcion and Immken, LaDonna and Janssens, Sandra and Jones, Kristi J and Keena, Beth A and Kochhar, Aaina and Liebelt, Jan and Martir-Negron, Arelis and Mahoney, Maurice J and Maystadt, Isabelle and McDougall, Carey and McEntagart, Meriel and Mendelsohn, Nancy and Miller, David T and Mortier, Geert and Morton, Jenny and Pappas, John and Plotkin, Scott R and Pond, Dinel and Rosenbaum, Kenneth and Rubin, Karol and Russell, Laura and Rutledge, Lane S and Saletti, Veronica and Schonberg, Rhonda and Schreiber, Allison and Seidel, Meredith and Siqveland, Elizabeth and Stockton, David W and Trevisson, Eva and Ullrich, Nicole J and Upadhyaya, Meena and van Minkelen, Rick and VERHELST, HELENE and Wallace, Margaret R and Yap, Yoon-Sim and Zackai, Elaine and Zonana, Jonathan and Zurcher, Vickie and Claes, Kathleen and Martin, Yolanda and Korf, Bruce R and Legius, Eric and Messiaen, Ludwine M},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {NEUROFIBROMATOSIS TYPE-I,OPTIC PATHWAY GLIOMAS,NERVE SHEATH TUMORS,SOUTH EAST WALES,NOONAN-SYNDROME,VONRECKLINGHAUSEN NEUROFIBROMATOSIS,SPINAL NEUROFIBROMATOSIS,PLEXIFORM NEUROFIBROMAS,TYPE-1 NEUROFIBROMATOSIS,NATURAL-HISTORY},
  language     = {eng},
  number       = {1},
  pages        = {69--87},
  title        = {Genotype-phenotype correlation in NF1 : evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844--848},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2017.12.001},
  volume       = {102},
  year         = {2017},
}

Chicago
Koczkowska, Magdalena, Yunjia Chen, Tom Callens, Alicia Gomes, Angela Sharp, Sherrell Johnson, Meng-Chang Hsiao, et al. 2017. “Genotype-phenotype Correlation in NF1 : Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848.” American Journal of Human Genetics 102 (1): 69–87.
APA
Koczkowska, M., Chen, Y., Callens, T., Gomes, A., Sharp, A., Johnson, S., Hsiao, M.-C., et al. (2017). Genotype-phenotype correlation in NF1 : evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844–848. AMERICAN JOURNAL OF HUMAN GENETICS, 102(1), 69–87.
Vancouver
1.
Koczkowska M, Chen Y, Callens T, Gomes A, Sharp A, Johnson S, et al. Genotype-phenotype correlation in NF1 : evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844–848. AMERICAN JOURNAL OF HUMAN GENETICS. 2017;102(1):69–87.
MLA
Koczkowska, Magdalena, Yunjia Chen, Tom Callens, et al. “Genotype-phenotype Correlation in NF1 : Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848.” AMERICAN JOURNAL OF HUMAN GENETICS 102.1 (2017): 69–87. Print.