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High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation

(2015) HUMAN MUTATION. 36(11). p.1052-1063
Author
Organization
Abstract
Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P<0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.
Keywords
neurofibromatosis type 1, NF1, p, Arg1809, phenotype-genotype correlations, Legius syndrome, NEUROFIBROMATOSIS TYPE-1 PATIENTS, OPTIC PATHWAY TUMORS, OF-THE-LITERATURE, SOUTH EAST WALES, VONRECKLINGHAUSEN NEUROFIBROMATOSIS, CARDIOVASCULAR MALFORMATIONS, LEGIUS SYNDROME, GENE, DELETIONS, STANDARDS

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Citation

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MLA
Rojnueangnit, Kitiwan et al. “High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients Carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-phenotype Correlation.” HUMAN MUTATION 36.11 (2015): 1052–1063. Print.
APA
Rojnueangnit, K., Xie, J., Gomes, A., Sharp, A., Callens, T., Chen, Y., Liu, Y., et al. (2015). High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation. HUMAN MUTATION, 36(11), 1052–1063.
Chicago author-date
Rojnueangnit, Kitiwan, Jing Xie, Alicia Gomes, Angela Sharp, Tom Callens, Yunjia Chen, Ying Liu, et al. 2015. “High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients Carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-phenotype Correlation.” Human Mutation 36 (11): 1052–1063.
Chicago author-date (all authors)
Rojnueangnit, Kitiwan, Jing Xie, Alicia Gomes, Angela Sharp, Tom Callens, Yunjia Chen, Ying Liu, Meagan Cochran, Mary-Alice Abbott, Joan Atkin, Dusica Babovic-Vuksanovic, Christopher P Barnett, Melissa Crenshaw, Dennis W Bartholomew, Lina Basel, Gary Bellus, Shay Ben-Shachar, Martin G Bialer, David Bick, Bruce Blumberg, Fanny Cortes, Karen L David, Anne Destree, Anna Duat-Rodriguez, Dawn Earl, Luis Escobar, Marthanda Eswara, Begona Ezquieta, Ian M Frayling, Moshe Frydman, Kathy Gardner, Karen W Gripp, Concepcion Hernández-Chico, Kurt Heyrman, Jennifer Ibrahim, Sandra Janssens, Beth A Keena, Isabel Llano-Rivas, Kathy Leppig, Marie McDonald, Vinod K Misra, Jennifer Mulbury, Vinodh Narayanan, Naama Orenstein, Patricia Galvin-Parton, Helio Pedro, Eniko K Pivnick, Cynthia M Powell, Linda Randolph, Salmo Raskin, Jordi Rosell, Karol Rubin, Margretta Seashore, Christian P Schaaf, Angela Scheuerle, Meredith Schultz, Elizabeth Schorry, Rhonda Schnur, Elizabeth Siqveland, Amanda Tkachuk, James Tonsgard, Meena Upadhyaya, Ishwar C Verma, Stephanie Wallace, Charles Williams, Elaine Zackai, Jonathan Zonana, Conxi Lazaro, Kathleen Claes, Bruce Korf, Yolanda Martin, Eric Legius, and Ludwine Messiaen. 2015. “High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients Carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-phenotype Correlation.” Human Mutation 36 (11): 1052–1063.
Vancouver
1.
Rojnueangnit K, Xie J, Gomes A, Sharp A, Callens T, Chen Y, et al. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation. HUMAN MUTATION. 2015;36(11):1052–63.
IEEE
[1]
K. Rojnueangnit et al., “High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation,” HUMAN MUTATION, vol. 36, no. 11, pp. 1052–1063, 2015.
@article{7082495,
  abstract     = {Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P<0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.},
  author       = {Rojnueangnit, Kitiwan and Xie, Jing and Gomes, Alicia and Sharp, Angela and Callens, Tom and Chen, Yunjia and Liu, Ying and Cochran, Meagan and Abbott, Mary-Alice and Atkin, Joan and Babovic-Vuksanovic, Dusica and Barnett, Christopher P and Crenshaw, Melissa and Bartholomew, Dennis W and Basel, Lina and Bellus, Gary and Ben-Shachar, Shay and Bialer, Martin G and Bick, David and Blumberg, Bruce and Cortes, Fanny and David, Karen L and Destree, Anne and Duat-Rodriguez, Anna and Earl, Dawn and Escobar, Luis and Eswara, Marthanda and Ezquieta, Begona and Frayling, Ian M and Frydman, Moshe and Gardner, Kathy and Gripp, Karen W and Hernández-Chico, Concepcion and Heyrman, Kurt and Ibrahim, Jennifer and Janssens, Sandra and Keena, Beth A and Llano-Rivas, Isabel and Leppig, Kathy and McDonald, Marie and Misra, Vinod K and Mulbury, Jennifer and Narayanan, Vinodh and Orenstein, Naama and Galvin-Parton, Patricia and Pedro, Helio and Pivnick, Eniko K and Powell, Cynthia M and Randolph, Linda and Raskin, Salmo and Rosell, Jordi and Rubin, Karol and Seashore, Margretta and Schaaf, Christian P and Scheuerle, Angela and Schultz, Meredith and Schorry, Elizabeth and Schnur, Rhonda and Siqveland, Elizabeth and Tkachuk, Amanda and Tonsgard, James and Upadhyaya, Meena and Verma, Ishwar C and Wallace, Stephanie and Williams, Charles and Zackai, Elaine and Zonana, Jonathan and Lazaro, Conxi and Claes, Kathleen and Korf, Bruce and Martin, Yolanda and Legius, Eric and Messiaen, Ludwine},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  keywords     = {neurofibromatosis type 1,NF1,p,Arg1809,phenotype-genotype correlations,Legius syndrome,NEUROFIBROMATOSIS TYPE-1 PATIENTS,OPTIC PATHWAY TUMORS,OF-THE-LITERATURE,SOUTH EAST WALES,VONRECKLINGHAUSEN NEUROFIBROMATOSIS,CARDIOVASCULAR MALFORMATIONS,LEGIUS SYNDROME,GENE,DELETIONS,STANDARDS},
  language     = {eng},
  number       = {11},
  pages        = {1052--1063},
  title        = {High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation},
  url          = {http://dx.doi.org/10.1002/humu.22832},
  volume       = {36},
  year         = {2015},
}

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