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

Magdalena Koczkowska, 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 CunninghamM. 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 J.M. 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 B.M. Claes, Marica Eoli, Yolanda Martin, Katharina Wimmer, Alessandro De Luca, Eric Legius, Ludwine M. Messiaen

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)299-315
Number of pages17
JournalHuman mutation
Volume41
Issue number1
DOIs
StatePublished - Jan 1 2020

Fingerprint

Neurofibroma
Neurofibromatosis 1
Plexiform Neurofibroma
Optic Nerve Glioma
Cardiovascular Abnormalities
Phenotype
Pulmonary Valve Stenosis
Counseling
Confidence Intervals
Population

Keywords

  • NF1
  • genotype–phenotype correlation
  • p.Arg1276
  • p.Lys1423
  • p.Met1149

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423 : genotype–phenotype study in neurofibromatosis type 1. / Koczkowska, Magdalena; Callens, Tom; Chen, Yunjia; Gomes, Alicia; Hicks, Alesha D.; Sharp, Angela; Johns, Eric; Uhas, Kim Armfield; Armstrong, Linlea; Bosanko, Katherine Armstrong; Babovic-Vuksanovic, Dusica; Baker, Laura; Basel, Donald G.; Bengala, Mario; Bennett, James T.; Chambers, Chelsea; Clarkson, Lola K.; Clementi, Maurizio; Cortés, Fanny M.; Cunningham, Mitch; D'Agostino, M. Daniela; Delatycki, Martin B.; Digilio, Maria C.; Dosa, Laura; Esposito, Silvia; Fox, Stephanie; Freckmann, Mary Louise; Fauth, Christine; Giugliano, Teresa; Giustini, Sandra; Goetsch, Allison; Goldberg, Yael; Greenwood, Robert S.; Griffis, Cristin; Gripp, Karen W.; Gupta, Punita; Haan, Eric; Hachen, Rachel K.; Haygarth, Tamara L.; Hernández-Chico, Concepción; Hodge, Katelyn; Hopkin, Robert J.; Hudgins, Louanne; Janssens, Sandra; Keller, Kory; Kelly-Mancuso, Geraldine; Kochhar, Aaina; Korf, Bruce R.; Lewis, Andrea M.; Liebelt, Jan; Lichty, Angie; Listernick, Robert H.; Lyons, Michael J.; Maystadt, Isabelle; Martinez Ojeda, Mayra; McDougall, Carey; McGregor, Lesley K.; Melis, Daniela; Mendelsohn, Nancy; Nowaczyk, Malgorzata J.M.; Ortenberg, June; Panzer, Karin; Pappas, John G.; Pierpont, Mary Ella; Piluso, Giulio; Pinna, Valentina; Pivnick, Eniko K.; Pond, Dinel A.; Powell, Cynthia M.; Rogers, Caleb; Ruhrman Shahar, Noa; Rutledge, S. Lane; Saletti, Veronica; Sandaradura, Sarah A.; Santoro, Claudia; Schatz, Ulrich A.; Schreiber, Allison; Scott, Daryl A.; Sellars, Elizabeth A.; Sheffer, Ruth; Siqveland, Elizabeth; Slopis, John M.; Smith, Rosemarie; Spalice, Alberto; Stockton, David W.; Streff, Haley; Theos, Amy; Tomlinson, Gail E.; Tran, Grace; Trapane, Pamela L.; Trevisson, Eva; Ullrich, Nicole J.; Van den Ende, Jenneke; Schrier Vergano, Samantha A.; Wallace, Stephanie E.; Wangler, Michael F.; Weaver, David D.; Yohay, Kaleb H.; Zackai, Elaine; Zonana, Jonathan; Zurcher, Vickie; Claes, Kathleen B.M.; Eoli, Marica; Martin, Yolanda; Wimmer, Katharina; De Luca, Alessandro; Legius, Eric; Messiaen, Ludwine M.

In: Human mutation, Vol. 41, No. 1, 01.01.2020, p. 299-315.

Research output: Contribution to journalArticle

Koczkowska, M, Callens, T, Chen, Y, Gomes, A, Hicks, AD, Sharp, A, Johns, E, Uhas, KA, Armstrong, L, Bosanko, KA, Babovic-Vuksanovic, D, Baker, L, Basel, DG, Bengala, M, Bennett, JT, Chambers, C, Clarkson, LK, Clementi, M, Cortés, FM, Cunningham, M, D'Agostino, MD, Delatycki, MB, Digilio, MC, Dosa, L, Esposito, S, Fox, S, Freckmann, ML, Fauth, C, Giugliano, T, Giustini, S, Goetsch, A, Goldberg, Y, Greenwood, RS, Griffis, C, Gripp, KW, Gupta, P, Haan, E, Hachen, RK, Haygarth, TL, Hernández-Chico, C, Hodge, K, Hopkin, RJ, Hudgins, L, Janssens, S, Keller, K, Kelly-Mancuso, G, Kochhar, A, Korf, BR, Lewis, AM, Liebelt, J, Lichty, A, Listernick, RH, Lyons, MJ, Maystadt, I, Martinez Ojeda, M, McDougall, C, McGregor, LK, Melis, D, Mendelsohn, N, Nowaczyk, MJM, Ortenberg, J, Panzer, K, Pappas, JG, Pierpont, ME, Piluso, G, Pinna, V, Pivnick, EK, Pond, DA, Powell, CM, Rogers, C, Ruhrman Shahar, N, Rutledge, SL, Saletti, V, Sandaradura, SA, Santoro, C, Schatz, UA, Schreiber, A, Scott, DA, Sellars, EA, Sheffer, R, Siqveland, E, Slopis, JM, Smith, R, Spalice, A, Stockton, DW, Streff, H, Theos, A, Tomlinson, GE, Tran, G, Trapane, PL, Trevisson, E, Ullrich, NJ, Van den Ende, J, Schrier Vergano, SA, Wallace, SE, Wangler, MF, Weaver, DD, Yohay, KH, Zackai, E, Zonana, J, Zurcher, V, Claes, KBM, Eoli, M, Martin, Y, Wimmer, K, De Luca, A, Legius, E & Messiaen, LM 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, vol. 41, no. 1, pp. 299-315. https://doi.org/10.1002/humu.23929
Koczkowska, Magdalena ; Callens, Tom ; Chen, Yunjia ; Gomes, Alicia ; Hicks, Alesha D. ; Sharp, Angela ; Johns, Eric ; Uhas, Kim Armfield ; Armstrong, Linlea ; Bosanko, Katherine Armstrong ; Babovic-Vuksanovic, Dusica ; Baker, Laura ; Basel, Donald G. ; Bengala, Mario ; Bennett, James T. ; Chambers, Chelsea ; Clarkson, Lola K. ; Clementi, Maurizio ; Cortés, Fanny M. ; Cunningham, Mitch ; D'Agostino, M. Daniela ; Delatycki, Martin B. ; Digilio, Maria C. ; Dosa, Laura ; Esposito, Silvia ; Fox, Stephanie ; Freckmann, Mary Louise ; Fauth, Christine ; Giugliano, Teresa ; Giustini, Sandra ; Goetsch, Allison ; Goldberg, Yael ; Greenwood, Robert S. ; Griffis, Cristin ; Gripp, Karen W. ; Gupta, Punita ; Haan, Eric ; Hachen, Rachel K. ; Haygarth, Tamara L. ; Hernández-Chico, Concepción ; Hodge, Katelyn ; Hopkin, Robert J. ; Hudgins, Louanne ; Janssens, Sandra ; Keller, Kory ; Kelly-Mancuso, Geraldine ; Kochhar, Aaina ; Korf, Bruce R. ; Lewis, Andrea M. ; Liebelt, Jan ; Lichty, Angie ; Listernick, Robert H. ; Lyons, Michael J. ; Maystadt, Isabelle ; Martinez Ojeda, Mayra ; McDougall, Carey ; McGregor, Lesley K. ; Melis, Daniela ; Mendelsohn, Nancy ; Nowaczyk, Malgorzata J.M. ; Ortenberg, June ; Panzer, Karin ; Pappas, John G. ; Pierpont, Mary Ella ; Piluso, Giulio ; Pinna, Valentina ; Pivnick, Eniko K. ; Pond, Dinel A. ; Powell, Cynthia M. ; Rogers, Caleb ; Ruhrman Shahar, Noa ; Rutledge, S. Lane ; Saletti, Veronica ; Sandaradura, Sarah A. ; Santoro, Claudia ; Schatz, Ulrich A. ; Schreiber, Allison ; Scott, Daryl A. ; Sellars, Elizabeth A. ; Sheffer, Ruth ; Siqveland, Elizabeth ; Slopis, John M. ; Smith, Rosemarie ; Spalice, Alberto ; Stockton, David W. ; Streff, Haley ; Theos, Amy ; Tomlinson, Gail E. ; Tran, Grace ; Trapane, Pamela L. ; Trevisson, Eva ; Ullrich, Nicole J. ; Van den Ende, Jenneke ; Schrier Vergano, Samantha A. ; Wallace, Stephanie E. ; Wangler, Michael F. ; Weaver, David D. ; Yohay, Kaleb H. ; Zackai, Elaine ; Zonana, Jonathan ; Zurcher, Vickie ; Claes, Kathleen B.M. ; Eoli, Marica ; Martin, Yolanda ; Wimmer, Katharina ; De Luca, Alessandro ; Legius, Eric ; Messiaen, Ludwine M. / Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423 : genotype–phenotype study in neurofibromatosis type 1. In: Human mutation. 2020 ; Vol. 41, No. 1. pp. 299-315.
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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.",
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T1 - Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423

T2 - genotype–phenotype study in neurofibromatosis type 1

AU - Koczkowska, Magdalena

AU - Callens, Tom

AU - Chen, Yunjia

AU - Gomes, Alicia

AU - Hicks, Alesha D.

AU - Sharp, Angela

AU - Johns, Eric

AU - Uhas, Kim Armfield

AU - Armstrong, Linlea

AU - Bosanko, Katherine Armstrong

AU - Babovic-Vuksanovic, Dusica

AU - Baker, Laura

AU - Basel, Donald G.

AU - Bengala, Mario

AU - Bennett, James T.

AU - Chambers, Chelsea

AU - Clarkson, Lola K.

AU - Clementi, Maurizio

AU - Cortés, Fanny M.

AU - Cunningham, Mitch

AU - D'Agostino, M. Daniela

AU - Delatycki, Martin B.

AU - Digilio, Maria C.

AU - Dosa, Laura

AU - Esposito, Silvia

AU - Fox, Stephanie

AU - Freckmann, Mary Louise

AU - Fauth, Christine

AU - Giugliano, Teresa

AU - Giustini, Sandra

AU - Goetsch, Allison

AU - Goldberg, Yael

AU - Greenwood, Robert S.

AU - Griffis, Cristin

AU - Gripp, Karen W.

AU - Gupta, Punita

AU - Haan, Eric

AU - Hachen, Rachel K.

AU - Haygarth, Tamara L.

AU - Hernández-Chico, Concepción

AU - Hodge, Katelyn

AU - Hopkin, Robert J.

AU - Hudgins, Louanne

AU - Janssens, Sandra

AU - Keller, Kory

AU - Kelly-Mancuso, Geraldine

AU - Kochhar, Aaina

AU - Korf, Bruce R.

AU - Lewis, Andrea M.

AU - Liebelt, Jan

AU - Lichty, Angie

AU - Listernick, Robert H.

AU - Lyons, Michael J.

AU - Maystadt, Isabelle

AU - Martinez Ojeda, Mayra

AU - McDougall, Carey

AU - McGregor, Lesley K.

AU - Melis, Daniela

AU - Mendelsohn, Nancy

AU - Nowaczyk, Malgorzata J.M.

AU - Ortenberg, June

AU - Panzer, Karin

AU - Pappas, John G.

AU - Pierpont, Mary Ella

AU - Piluso, Giulio

AU - Pinna, Valentina

AU - Pivnick, Eniko K.

AU - Pond, Dinel A.

AU - Powell, Cynthia M.

AU - Rogers, Caleb

AU - Ruhrman Shahar, Noa

AU - Rutledge, S. Lane

AU - Saletti, Veronica

AU - Sandaradura, Sarah A.

AU - Santoro, Claudia

AU - Schatz, Ulrich A.

AU - Schreiber, Allison

AU - Scott, Daryl A.

AU - Sellars, Elizabeth A.

AU - Sheffer, Ruth

AU - Siqveland, Elizabeth

AU - Slopis, John M.

AU - Smith, Rosemarie

AU - Spalice, Alberto

AU - Stockton, David W.

AU - Streff, Haley

AU - Theos, Amy

AU - Tomlinson, Gail E.

AU - Tran, Grace

AU - Trapane, Pamela L.

AU - Trevisson, Eva

AU - Ullrich, Nicole J.

AU - Van den Ende, Jenneke

AU - Schrier Vergano, Samantha A.

AU - Wallace, Stephanie E.

AU - Wangler, Michael F.

AU - Weaver, David D.

AU - Yohay, Kaleb H.

AU - Zackai, Elaine

AU - Zonana, Jonathan

AU - Zurcher, Vickie

AU - Claes, Kathleen B.M.

AU - Eoli, Marica

AU - Martin, Yolanda

AU - Wimmer, Katharina

AU - De Luca, Alessandro

AU - Legius, Eric

AU - Messiaen, Ludwine M.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - NF1

KW - genotype–phenotype correlation

KW - p.Arg1276

KW - p.Lys1423

KW - p.Met1149

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