High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation

Kitiwan Rojnueangnit, 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 BlumbergFanny 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, Ludwine Messiaen

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 café-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.

Original languageEnglish (US)
Pages (from-to)1052-1063
Number of pages12
JournalHuman Mutation
Volume36
Issue number11
DOIs
StatePublished - Nov 1 2015

Fingerprint

Noonan Syndrome
Neurofibromatosis 1
Pulmonary Valve Stenosis
Genetic Association Studies
Missense Mutation
Incidence
Melanocytes
Plexiform Neurofibroma
Phenotype
Neurofibroma
Developmental Disabilities
Mutation
Inborn Genetic Diseases
Learning Disorders
Counseling
Exons
Skin

Keywords

  • Legius syndrome
  • Neurofibromatosis type 1
  • NF1
  • P.Arg1809
  • Phenotype-genotype correlations

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809 : Genotype-Phenotype Correlation. / Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary Alice; Atkin, Joan; Babovic-Vuksanovic, Dusica; Barnett, Christopher P.; Crenshaw, Melissa; Bartholomew, Dennis W.; Basel, Lina; Bellus, Gary; Ben-Shachar, Shay; Bialer, Martin G.; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L.; Destree, Anne; Duat-Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M.; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W.; Hernández-Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A.; Llano-Rivas, Isabel; Leppig, Kathy; Mcdonald, Marie; Misra, Vinod K.; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin-Parton, Patricia; Pedro, Helio; Pivnick, Eniko K.; Powell, Cynthia M.; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P.; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C.; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine.

In: Human Mutation, Vol. 36, No. 11, 01.11.2015, p. 1052-1063.

Research output: Contribution to journalArticle

Rojnueangnit, K, Xie, J, Gomes, A, Sharp, A, Callens, T, Chen, Y, Liu, Y, Cochran, M, Abbott, MA, Atkin, J, Babovic-Vuksanovic, D, Barnett, CP, Crenshaw, M, Bartholomew, DW, Basel, L, Bellus, G, Ben-Shachar, S, Bialer, MG, Bick, D, Blumberg, B, Cortes, F, David, KL, Destree, A, Duat-Rodriguez, A, Earl, D, Escobar, L, Eswara, M, Ezquieta, B, Frayling, IM, Frydman, M, Gardner, K, Gripp, KW, Hernández-Chico, C, Heyrman, K, Ibrahim, J, Janssens, S, Keena, BA, Llano-Rivas, I, Leppig, K, Mcdonald, M, Misra, VK, Mulbury, J, Narayanan, V, Orenstein, N, Galvin-Parton, P, Pedro, H, Pivnick, EK, Powell, CM, Randolph, L, Raskin, S, Rosell, J, Rubin, K, Seashore, M, Schaaf, CP, Scheuerle, A, Schultz, M, Schorry, E, Schnur, R, Siqveland, E, Tkachuk, A, Tonsgard, J, Upadhyaya, M, Verma, IC, Wallace, S, Williams, C, Zackai, E, Zonana, J, Lazaro, C, Claes, K, Korf, B, Martin, Y, Legius, E & Messiaen, L 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, vol. 36, no. 11, pp. 1052-1063. https://doi.org/10.1002/humu.22832
Rojnueangnit, Kitiwan ; Xie, Jing ; Gomes, Alicia ; Sharp, Angela ; Callens, Tom ; Chen, Yunjia ; Liu, Ying ; Cochran, Meagan ; Abbott, Mary Alice ; Atkin, Joan ; Babovic-Vuksanovic, Dusica ; Barnett, Christopher P. ; Crenshaw, Melissa ; Bartholomew, Dennis W. ; Basel, Lina ; Bellus, Gary ; Ben-Shachar, Shay ; Bialer, Martin G. ; Bick, David ; Blumberg, Bruce ; Cortes, Fanny ; David, Karen L. ; Destree, Anne ; Duat-Rodriguez, Anna ; Earl, Dawn ; Escobar, Luis ; Eswara, Marthanda ; Ezquieta, Begona ; Frayling, Ian M. ; Frydman, Moshe ; Gardner, Kathy ; Gripp, Karen W. ; Hernández-Chico, Concepcion ; Heyrman, Kurt ; Ibrahim, Jennifer ; Janssens, Sandra ; Keena, Beth A. ; Llano-Rivas, Isabel ; Leppig, Kathy ; Mcdonald, Marie ; Misra, Vinod K. ; Mulbury, Jennifer ; Narayanan, Vinodh ; Orenstein, Naama ; Galvin-Parton, Patricia ; Pedro, Helio ; Pivnick, Eniko K. ; Powell, Cynthia M. ; Randolph, Linda ; Raskin, Salmo ; Rosell, Jordi ; Rubin, Karol ; Seashore, Margretta ; Schaaf, Christian P. ; Scheuerle, Angela ; Schultz, Meredith ; Schorry, Elizabeth ; Schnur, Rhonda ; Siqveland, Elizabeth ; Tkachuk, Amanda ; Tonsgard, James ; Upadhyaya, Meena ; Verma, Ishwar C. ; Wallace, Stephanie ; Williams, Charles ; Zackai, Elaine ; Zonana, Jonathan ; Lazaro, Conxi ; Claes, Kathleen ; Korf, Bruce ; Martin, Yolanda ; Legius, Eric ; Messiaen, Ludwine. / High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809 : Genotype-Phenotype Correlation. In: Human Mutation. 2015 ; Vol. 36, No. 11. pp. 1052-1063.
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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 caf{\'e}-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.",
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T1 - High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809

T2 - Genotype-Phenotype Correlation

AU - Rojnueangnit, Kitiwan

AU - Xie, Jing

AU - Gomes, Alicia

AU - Sharp, Angela

AU - Callens, Tom

AU - Chen, Yunjia

AU - Liu, Ying

AU - Cochran, Meagan

AU - Abbott, Mary Alice

AU - Atkin, Joan

AU - Babovic-Vuksanovic, Dusica

AU - Barnett, Christopher P.

AU - Crenshaw, Melissa

AU - Bartholomew, Dennis W.

AU - Basel, Lina

AU - Bellus, Gary

AU - Ben-Shachar, Shay

AU - Bialer, Martin G.

AU - Bick, David

AU - Blumberg, Bruce

AU - Cortes, Fanny

AU - David, Karen L.

AU - Destree, Anne

AU - Duat-Rodriguez, Anna

AU - Earl, Dawn

AU - Escobar, Luis

AU - Eswara, Marthanda

AU - Ezquieta, Begona

AU - Frayling, Ian M.

AU - Frydman, Moshe

AU - Gardner, Kathy

AU - Gripp, Karen W.

AU - Hernández-Chico, Concepcion

AU - Heyrman, Kurt

AU - Ibrahim, Jennifer

AU - Janssens, Sandra

AU - Keena, Beth A.

AU - Llano-Rivas, Isabel

AU - Leppig, Kathy

AU - Mcdonald, Marie

AU - Misra, Vinod K.

AU - Mulbury, Jennifer

AU - Narayanan, Vinodh

AU - Orenstein, Naama

AU - Galvin-Parton, Patricia

AU - Pedro, Helio

AU - Pivnick, Eniko K.

AU - Powell, Cynthia M.

AU - Randolph, Linda

AU - Raskin, Salmo

AU - Rosell, Jordi

AU - Rubin, Karol

AU - Seashore, Margretta

AU - Schaaf, Christian P.

AU - Scheuerle, Angela

AU - Schultz, Meredith

AU - Schorry, Elizabeth

AU - Schnur, Rhonda

AU - Siqveland, Elizabeth

AU - Tkachuk, Amanda

AU - Tonsgard, James

AU - Upadhyaya, Meena

AU - Verma, Ishwar C.

AU - Wallace, Stephanie

AU - Williams, Charles

AU - Zackai, Elaine

AU - Zonana, Jonathan

AU - Lazaro, Conxi

AU - Claes, Kathleen

AU - Korf, Bruce

AU - Martin, Yolanda

AU - Legius, Eric

AU - Messiaen, Ludwine

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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 café-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.

AB - 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 café-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.

KW - Legius syndrome

KW - Neurofibromatosis type 1

KW - NF1

KW - P.Arg1809

KW - Phenotype-genotype correlations

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