Advanced search
1 file | 640.01 KB Add to list

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

Author
Organization
Abstract
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
Keywords
genotype-phenotype correlation, NF1, p, Arg1276, p, Lys1423, p, Met1149, OPTIC PATHWAY TUMORS, SOUTH EAST WALES, AU-LAIT SPOTS, NOONAN-SYNDROME, VONRECKLINGHAUSEN NEUROFIBROMATOSIS, SPINAL NEUROFIBROMATOSIS, PULMONARY STENOSIS, NATURAL-HISTORY, INDEPENDENT NF1, MUTATIONS

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 640.01 KB

Citation

Please use this url to cite or link to this publication:

MLA
Koczkowska, Magdalena, et al. “Clinical Spectrum of Individuals with Pathogenic NF1 Missense Variants Affecting p.Met1149, p.Arg1276, and p.Lys1423: Genotype-Phenotype Study in Neurofibromatosis Type 1.” HUMAN MUTATION, 2020.
APA
Koczkowska, M., Callens, T., Chen, Y., Gomes, A., Hicks, A. D., Sharp, A., … Messiaen, L. M. (2020). Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. HUMAN MUTATION.
Chicago author-date
Koczkowska, Magdalena, Tom Callens, Yunjia Chen, Alicia Gomes, Alesha D Hicks, Angela Sharp, Eric Johns, et al. 2020. “Clinical Spectrum of Individuals with Pathogenic NF1 Missense Variants Affecting p.Met1149, p.Arg1276, and p.Lys1423: Genotype-Phenotype Study in Neurofibromatosis Type 1.” HUMAN MUTATION.
Chicago author-date (all authors)
Koczkowska, Magdalena, Tom Callens, Yunjia Chen, Alicia Gomes, Alesha D Hicks, Angela Sharp, Eric Johns, Kim Armfield Uhas, Linlea Armstrong, Katherine Armstrong Bosanko, Dusica Babovic‐Vuksanovic, Laura Baker, Donald G Basel, Mario Bengala, James T Bennett, Chelsea Chambers, Lola K Clarkson, Maurizio Clementi, Fanny M Cortés, Mitch Cunningham, M Daniela D’Agostino, Martin B Delatycki, Maria C Digilio, Laura Dosa, Silvia Esposito, Stephanie Fox, Mary‐Louise Freckmann, Christine Fauth, Teresa Giugliano, Sandra Giustini, Allison Goetsch, Yael Goldberg, Robert S Greenwood, Cristin Griffis, Karen W Gripp, Punita Gupta, Eric Haan, Rachel K Hachen, Tamara L Haygarth, Concepción Hernández‐Chico, Katelyn Hodge, Robert J Hopkin, Louanne Hudgins, Sandra Janssens, Kory Keller, Geraldine Kelly‐Mancuso, Aaina Kochhar, Bruce R Korf, Andrea M Lewis, Jan Liebelt, Angie Lichty, Robert H Listernick, Michael J Lyons, Isabelle Maystadt, Mayra Martinez Ojeda, Carey McDougall, Lesley K. McGregor, Daniela Melis, Nancy Mendelsohn, Malgorzata JM Nowaczyk, June Ortenberg, Karin Panzer, John G Pappas, Mary Ella Pierpont, Giulio Piluso, Valentina Pinna, Eniko K Pivnick, Dinel A Pond, Cynthia M Powell, Caleb Rogers, Noa Ruhrman Shahar, S Lane Rutledge, Veronica Saletti, Sarah A Sandaradura, Claudia Santoro, Ulrich A Schatz, Allison Schreiber, Daryl A Scott, Elizabeth A Sellars, Ruth Sheffer, Elizabeth Siqveland, John M Slopis, Rosemarie Smith, Alberto Spalice, David W Stockton, Haley Streff, Amy Theos, Gail E Tomlinson, Grace Tran, Pamela L Trapane, Eva Trevisson, Nicole J Ullrich, Jenneke Van den Ende, Samantha A Schrier Vergano, Stephanie E Wallace, Michael F Wangler, David D Weaver, Kaleb H Yohay, Elaine Zackai, Jonathan Zonana, Vickie Zurcher, Kathleen Claes, Marica Eoli, Yolanda Martin, Katharina Wimmer, Alessandro De Luca, Eric Legius, and Ludwine M Messiaen. 2020. “Clinical Spectrum of Individuals with Pathogenic NF1 Missense Variants Affecting p.Met1149, p.Arg1276, and p.Lys1423: Genotype-Phenotype Study in Neurofibromatosis Type 1.” HUMAN MUTATION.
Vancouver
1.
Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. HUMAN MUTATION. 2020;
IEEE
[1]
M. Koczkowska et al., “Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1,” HUMAN MUTATION, 2020.
@article{8632274,
  abstract     = {We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.},
  author       = {Koczkowska, Magdalena and Callens, Tom and Chen, Yunjia and Gomes, Alicia and Hicks, Alesha D and Sharp, Angela and Johns, Eric and Uhas, Kim Armfield and Armstrong, Linlea and Bosanko, Katherine Armstrong and Babovic‐Vuksanovic, Dusica and Baker, Laura and Basel, Donald G and Bengala, Mario and Bennett, James T and Chambers, Chelsea and Clarkson, Lola K and Clementi, Maurizio and Cortés, Fanny M and Cunningham, Mitch and D'Agostino, M Daniela and Delatycki, Martin B and Digilio, Maria C and Dosa, Laura and Esposito, Silvia and Fox, Stephanie and Freckmann, Mary‐Louise and Fauth, Christine and Giugliano, Teresa and Giustini, Sandra and Goetsch, Allison and Goldberg, Yael and Greenwood, Robert S and Griffis, Cristin and Gripp, Karen W and Gupta, Punita and Haan, Eric and Hachen, Rachel K and Haygarth, Tamara L and Hernández‐Chico, Concepción and Hodge, Katelyn and Hopkin, Robert J and Hudgins, Louanne and Janssens, Sandra and Keller, Kory and Kelly‐Mancuso, Geraldine and Kochhar, Aaina and Korf, Bruce R and Lewis, Andrea M and Liebelt, Jan and Lichty, Angie and Listernick, Robert H and Lyons, Michael J and Maystadt, Isabelle and Ojeda, Mayra Martinez and McDougall, Carey and McGregor, Lesley K. and Melis, Daniela and Mendelsohn, Nancy and Nowaczyk, Malgorzata JM and Ortenberg, June and Panzer, Karin and Pappas, John G and Pierpont, Mary Ella and Piluso, Giulio and Pinna, Valentina and Pivnick, Eniko K and Pond, Dinel A and Powell, Cynthia M and Rogers, Caleb and Shahar, Noa Ruhrman and Rutledge, S Lane and Saletti, Veronica and Sandaradura, Sarah A and Santoro, Claudia and Schatz, Ulrich A and Schreiber, Allison and Scott, Daryl A and Sellars, Elizabeth A and Sheffer, Ruth and Siqveland, Elizabeth and Slopis, John M and Smith, Rosemarie and Spalice, Alberto and Stockton, David W and Streff, Haley and Theos, Amy and Tomlinson, Gail E and Tran, Grace and Trapane, Pamela L and Trevisson, Eva and Ullrich, Nicole J and Van den Ende, Jenneke and Schrier Vergano, Samantha A and Wallace, Stephanie E and Wangler, Michael F and Weaver, David D and Yohay, Kaleb H and Zackai, Elaine and Zonana, Jonathan and Zurcher, Vickie and Claes, Kathleen and Eoli, Marica and Martin, Yolanda and Wimmer, Katharina and De Luca, Alessandro and Legius, Eric and Messiaen, Ludwine M},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  keywords     = {genotype-phenotype correlation,NF1,p,Arg1276,p,Lys1423,p,Met1149,OPTIC PATHWAY TUMORS,SOUTH EAST WALES,AU-LAIT SPOTS,NOONAN-SYNDROME,VONRECKLINGHAUSEN NEUROFIBROMATOSIS,SPINAL NEUROFIBROMATOSIS,PULMONARY STENOSIS,NATURAL-HISTORY,INDEPENDENT NF1,MUTATIONS},
  language     = {eng},
  title        = {Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1},
  url          = {http://dx.doi.org/10.1002/humu.23929},
  year         = {2020},
}

Altmetric
View in Altmetric
Web of Science
Times cited: