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

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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.
Keywords
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

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MLA
Koczkowska, Magdalena, 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, vol. 102, no. 1, 2018, pp. 69–87, doi:10.1016/j.ajhg.2017.12.001.
APA
Koczkowska, M., Chen, Y., Callens, T., Gomes, A., Sharp, A., Johnson, S., … Messiaen, L. M. (2018). 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. https://doi.org/10.1016/j.ajhg.2017.12.001
Chicago author-date
Koczkowska, Magdalena, Yunjia Chen, Tom Callens, Alicia Gomes, Angela Sharp, Sherrell Johnson, Meng-Chang Hsiao, et al. 2018. “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. https://doi.org/10.1016/j.ajhg.2017.12.001.
Chicago author-date (all authors)
Koczkowska, Magdalena, Yunjia Chen, Tom Callens, Alicia Gomes, Angela Sharp, Sherrell Johnson, Meng-Chang Hsiao, Zhenbin Chen, Meena Balasubramanian, Christopher P Barnett, Troy A Becker, Shay Ben-Shachar, Debora R Bertola, Jaishri O Blakeley, Emma MM Burkitt-Wright, Alison Callaway, Melissa Crenshaw, Karin S Cunha, Mitch Cunningham, Maria D D’Agostino, Karin Dahan, Alessandro De Luca, Anne Destrée, Radhika Dhamija, Marica Eoli, D Gareth R Evans, Patricia Galvin-Parton, Jaya K George-Abraham, Karen W Gripp, Jose Guevara-Campos, Neil A Hanchard, Concepcion Hernández-Chico, LaDonna Immken, Sandra Janssens, Kristi J Jones, Beth A Keena, Aaina Kochhar, Jan Liebelt, Arelis Martir-Negron, Maurice J Mahoney, Isabelle Maystadt, Carey McDougall, Meriel McEntagart, Nancy Mendelsohn, David T Miller, Geert Mortier, Jenny Morton, John Pappas, Scott R Plotkin, Dinel Pond, Kenneth Rosenbaum, Karol Rubin, Laura Russell, Lane S Rutledge, Veronica Saletti, Rhonda Schonberg, Allison Schreiber, Meredith Seidel, Elizabeth Siqveland, David W Stockton, Eva Trevisson, Nicole J Ullrich, Meena Upadhyaya, Rick van Minkelen, Helene Verhelst, Margaret R Wallace, Yoon-Sim Yap, Elaine Zackai, Jonathan Zonana, Vickie Zurcher, Kathleen Claes, Yolanda Martin, Bruce R Korf, Eric Legius, and Ludwine M Messiaen. 2018. “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. doi:10.1016/j.ajhg.2017.12.001.
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. 2018;102(1):69–87.
IEEE
[1]
M. Koczkowska 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, vol. 102, no. 1, pp. 69–87, 2018.
@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 < 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’Agostino, Maria D and Dahan, Karin and De Luca, Alessandro and Destrée, 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 Hernández-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}},
  keywords     = {{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         = {{2018}},
}

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