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, Troy A. Becker, Shay Ben-Shachar, Debora R. Bertola, Jaishri O. Blakeley, Emma M.M. Burkitt-Wright, Alison Callaway, Melissa Crenshaw, Karin S. Cunha, Mitch Cunningham, Maria D. D'AgostinoKarin 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, La Donna 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 (Jon) Zonana, Vickie Zurcher, Kathleen Claes, Yolanda Martin, Bruce R. Korf, Eric Legius, Ludwine M. Messiaen

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 ∼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.

Original languageEnglish (US)
Pages (from-to)69-87
Number of pages19
JournalAmerican Journal of Human Genetics
Volume102
Issue number1
DOIs
StatePublished - Jan 4 2018

Fingerprint

Neurofibromatosis 1
Genetic Association Studies
Missense Mutation
Codon
Phenotype
Plexiform Neurofibroma
Optic Nerve Glioma
Neurofibroma
Inborn Genetic Diseases
Genetic Counseling
Serine
Cysteine
Neoplasms
Parturition
Amino Acids
Skin
Mutation
Incidence

Keywords

  • codons 844–848
  • CSRD
  • genotype-phenotype correlation
  • missense mutation
  • MPNST
  • neurofibromatosis type 1
  • NF1
  • plexiform neurofibroma
  • spinal NF

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genotype-Phenotype Correlation in NF1 : Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848. / Koczkowska, Magdalena; Chen, Yunjia; Callens, Tom; Gomes, Alicia; Sharp, Angela; Johnson, Sherrell; Hsiao, Meng Chang; Chen, Zhenbin; Balasubramanian, Meena; Barnett, Christopher P.; Becker, Troy A.; Ben-Shachar, Shay; Bertola, Debora R.; Blakeley, Jaishri O.; Burkitt-Wright, Emma M.M.; Callaway, Alison; Crenshaw, Melissa; Cunha, Karin S.; Cunningham, Mitch; D'Agostino, Maria D.; Dahan, Karin; De Luca, Alessandro; Destrée, Anne; Dhamija, Radhika; Eoli, Marica; Evans, D. Gareth R.; Galvin-Parton, Patricia; George-Abraham, Jaya K.; Gripp, Karen W.; Guevara-Campos, Jose; Hanchard, Neil A.; Hernández-Chico, Concepcion; Immken, La Donna; Janssens, Sandra; Jones, Kristi J.; Keena, Beth A.; Kochhar, Aaina; Liebelt, Jan; Martir-Negron, Arelis; Mahoney, Maurice J.; Maystadt, Isabelle; McDougall, Carey; McEntagart, Meriel; Mendelsohn, Nancy; Miller, David T.; Mortier, Geert; Morton, Jenny; Pappas, John; Plotkin, Scott R.; Pond, Dinel; Rosenbaum, Kenneth; Rubin, Karol; Russell, Laura; Rutledge, Lane S.; Saletti, Veronica; Schonberg, Rhonda; Schreiber, Allison; Seidel, Meredith; Siqveland, Elizabeth; Stockton, David W.; Trevisson, Eva; Ullrich, Nicole J.; Upadhyaya, Meena; van Minkelen, Rick; Verhelst, Helene; Wallace, Margaret R.; Yap, Yoon Sim; Zackai, Elaine; Zonana, Jonathan (Jon); Zurcher, Vickie; Claes, Kathleen; Martin, Yolanda; Korf, Bruce R.; Legius, Eric; Messiaen, Ludwine M.

In: American Journal of Human Genetics, Vol. 102, No. 1, 04.01.2018, p. 69-87.

Research output: Contribution to journalArticle

Koczkowska, M, Chen, Y, Callens, T, Gomes, A, Sharp, A, Johnson, S, Hsiao, MC, Chen, Z, Balasubramanian, M, Barnett, CP, Becker, TA, Ben-Shachar, S, Bertola, DR, Blakeley, JO, Burkitt-Wright, EMM, Callaway, A, Crenshaw, M, Cunha, KS, Cunningham, M, D'Agostino, MD, Dahan, K, De Luca, A, Destrée, A, Dhamija, R, Eoli, M, Evans, DGR, Galvin-Parton, P, George-Abraham, JK, Gripp, KW, Guevara-Campos, J, Hanchard, NA, Hernández-Chico, C, Immken, LD, Janssens, S, Jones, KJ, Keena, BA, Kochhar, A, Liebelt, J, Martir-Negron, A, Mahoney, MJ, Maystadt, I, McDougall, C, McEntagart, M, Mendelsohn, N, Miller, DT, Mortier, G, Morton, J, Pappas, J, Plotkin, SR, Pond, D, Rosenbaum, K, Rubin, K, Russell, L, Rutledge, LS, Saletti, V, Schonberg, R, Schreiber, A, Seidel, M, Siqveland, E, Stockton, DW, Trevisson, E, Ullrich, NJ, Upadhyaya, M, van Minkelen, R, Verhelst, H, Wallace, MR, Yap, YS, Zackai, E, Zonana, JJ, Zurcher, V, Claes, K, Martin, Y, Korf, BR, Legius, E & Messiaen, LM 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, vol. 102, no. 1, pp. 69-87. https://doi.org/10.1016/j.ajhg.2017.12.001
Koczkowska, Magdalena ; Chen, Yunjia ; Callens, Tom ; Gomes, Alicia ; Sharp, Angela ; Johnson, Sherrell ; Hsiao, Meng Chang ; Chen, Zhenbin ; Balasubramanian, Meena ; Barnett, Christopher P. ; Becker, Troy A. ; Ben-Shachar, Shay ; Bertola, Debora R. ; Blakeley, Jaishri O. ; Burkitt-Wright, Emma M.M. ; Callaway, Alison ; Crenshaw, Melissa ; Cunha, Karin S. ; Cunningham, Mitch ; D'Agostino, Maria D. ; Dahan, Karin ; De Luca, Alessandro ; Destrée, Anne ; Dhamija, Radhika ; Eoli, Marica ; Evans, D. Gareth R. ; Galvin-Parton, Patricia ; George-Abraham, Jaya K. ; Gripp, Karen W. ; Guevara-Campos, Jose ; Hanchard, Neil A. ; Hernández-Chico, Concepcion ; Immken, La Donna ; Janssens, Sandra ; Jones, Kristi J. ; Keena, Beth A. ; Kochhar, Aaina ; Liebelt, Jan ; Martir-Negron, Arelis ; Mahoney, Maurice J. ; Maystadt, Isabelle ; McDougall, Carey ; McEntagart, Meriel ; Mendelsohn, Nancy ; Miller, David T. ; Mortier, Geert ; Morton, Jenny ; Pappas, John ; Plotkin, Scott R. ; Pond, Dinel ; Rosenbaum, Kenneth ; Rubin, Karol ; Russell, Laura ; Rutledge, Lane S. ; Saletti, Veronica ; Schonberg, Rhonda ; Schreiber, Allison ; Seidel, Meredith ; Siqveland, Elizabeth ; Stockton, David W. ; Trevisson, Eva ; Ullrich, Nicole J. ; Upadhyaya, Meena ; van Minkelen, Rick ; Verhelst, Helene ; Wallace, Margaret R. ; Yap, Yoon Sim ; Zackai, Elaine ; Zonana, Jonathan (Jon) ; Zurcher, Vickie ; Claes, Kathleen ; Martin, Yolanda ; Korf, Bruce R. ; Legius, Eric ; Messiaen, Ludwine M. / Genotype-Phenotype Correlation in NF1 : Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 1. pp. 69-87.
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title = "Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848",
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 ∼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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TY - JOUR

T1 - Genotype-Phenotype Correlation in NF1

T2 - Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

AU - Koczkowska, Magdalena

AU - Chen, Yunjia

AU - Callens, Tom

AU - Gomes, Alicia

AU - Sharp, Angela

AU - Johnson, Sherrell

AU - Hsiao, Meng Chang

AU - Chen, Zhenbin

AU - Balasubramanian, Meena

AU - Barnett, Christopher P.

AU - Becker, Troy A.

AU - Ben-Shachar, Shay

AU - Bertola, Debora R.

AU - Blakeley, Jaishri O.

AU - Burkitt-Wright, Emma M.M.

AU - Callaway, Alison

AU - Crenshaw, Melissa

AU - Cunha, Karin S.

AU - Cunningham, Mitch

AU - D'Agostino, Maria D.

AU - Dahan, Karin

AU - De Luca, Alessandro

AU - Destrée, Anne

AU - Dhamija, Radhika

AU - Eoli, Marica

AU - Evans, D. Gareth R.

AU - Galvin-Parton, Patricia

AU - George-Abraham, Jaya K.

AU - Gripp, Karen W.

AU - Guevara-Campos, Jose

AU - Hanchard, Neil A.

AU - Hernández-Chico, Concepcion

AU - Immken, La Donna

AU - Janssens, Sandra

AU - Jones, Kristi J.

AU - Keena, Beth A.

AU - Kochhar, Aaina

AU - Liebelt, Jan

AU - Martir-Negron, Arelis

AU - Mahoney, Maurice J.

AU - Maystadt, Isabelle

AU - McDougall, Carey

AU - McEntagart, Meriel

AU - Mendelsohn, Nancy

AU - Miller, David T.

AU - Mortier, Geert

AU - Morton, Jenny

AU - Pappas, John

AU - Plotkin, Scott R.

AU - Pond, Dinel

AU - Rosenbaum, Kenneth

AU - Rubin, Karol

AU - Russell, Laura

AU - Rutledge, Lane S.

AU - Saletti, Veronica

AU - Schonberg, Rhonda

AU - Schreiber, Allison

AU - Seidel, Meredith

AU - Siqveland, Elizabeth

AU - Stockton, David W.

AU - Trevisson, Eva

AU - Ullrich, Nicole J.

AU - Upadhyaya, Meena

AU - van Minkelen, Rick

AU - Verhelst, Helene

AU - Wallace, Margaret R.

AU - Yap, Yoon Sim

AU - Zackai, Elaine

AU - Zonana, Jonathan (Jon)

AU - Zurcher, Vickie

AU - Claes, Kathleen

AU - Martin, Yolanda

AU - Korf, Bruce R.

AU - Legius, Eric

AU - Messiaen, Ludwine M.

PY - 2018/1/4

Y1 - 2018/1/4

N2 - 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 ∼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.

AB - 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 ∼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.

KW - codons 844–848

KW - CSRD

KW - genotype-phenotype correlation

KW - missense mutation

KW - MPNST

KW - neurofibromatosis type 1

KW - NF1

KW - plexiform neurofibroma

KW - spinal NF

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