Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Magdalena Koczkowska, Tom Callens, Alicia Gomes, Angela Sharp, Yunjia Chen, Alesha D. Hicks, Arthur S. Aylsworth, Amedeo A. Azizi, Donald G. Basel, Gary Bellus, Lynne M. Bird, Maria A. Blazo, Leah W. Burke, Ashley Cannon, Felicity Collins, Colette DeFilippo, Ellen Denayer, Maria C. Digilio, Shelley K. Dills, Laura DosaRobert S. Greenwood, Cristin Griffis, Punita Gupta, Rachel K. Hachen, Concepción Hernández-Chico, Sandra Janssens, Kristi J. Jones, Justin T. Jordan, Peter Kannu, Bruce R. Korf, Andrea M. Lewis, Robert H. Listernick, Fortunato Lonardo, Maurice J. Mahoney, Mayra Martinez Ojeda, Marie T. McDonald, Carey McDougall, Nancy Mendelsohn, David T. Miller, Mari Mori, Rianne Oostenbrink, Sebastién Perreault, Mary Ella Pierpont, Carmelo Piscopo, Dinel A. Pond, Linda M. Randolph, Katherine A. Rauen, Surya Rednam, S. Lane Rutledge, Veronica Saletti, G. Bradley Schaefer, Elizabeth K. Schorry, Daryl A. Scott, Andrea Shugar, Elizabeth Siqveland, Lois J. Starr, Ashraf Syed, Pamela L. Trapane, Nicole J. Ullrich, Emily G. Wakefield, Laurence E. Walsh, Michael F. Wangler, Elaine Zackai, Kathleen B.M. Claes, Katharina Wimmer, Rick van Minkelen, Alessandro De Luca, Yolanda Martin, Eric Legius, Ludwine M. Messiaen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Original languageEnglish
JournalGenetics in Medicine
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Neurofibromatosis 1 Genes
Neurofibromatosis 1
Phenotype
Neurofibroma
Skin
Optic Nerve Glioma
Loss of Heterozygosity
Learning Disorders
Astrocytoma
Checklist
Brain Neoplasms
Microsatellite Repeats
Neoplasms
Learning

Keywords

  • genotype–phenotype correlation
  • learning difficulties
  • neurofibroma
  • NF1
  • p.Met992del

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del) : an update of genotype–phenotype correlation. / Koczkowska, Magdalena; Callens, Tom; Gomes, Alicia; Sharp, Angela; Chen, Yunjia; Hicks, Alesha D.; Aylsworth, Arthur S.; Azizi, Amedeo A.; Basel, Donald G.; Bellus, Gary; Bird, Lynne M.; Blazo, Maria A.; Burke, Leah W.; Cannon, Ashley; Collins, Felicity; DeFilippo, Colette; Denayer, Ellen; Digilio, Maria C.; Dills, Shelley K.; Dosa, Laura; Greenwood, Robert S.; Griffis, Cristin; Gupta, Punita; Hachen, Rachel K.; Hernández-Chico, Concepción; Janssens, Sandra; Jones, Kristi J.; Jordan, Justin T.; Kannu, Peter; Korf, Bruce R.; Lewis, Andrea M.; Listernick, Robert H.; Lonardo, Fortunato; Mahoney, Maurice J.; Ojeda, Mayra Martinez; McDonald, Marie T.; McDougall, Carey; Mendelsohn, Nancy; Miller, David T.; Mori, Mari; Oostenbrink, Rianne; Perreault, Sebastién; Pierpont, Mary Ella; Piscopo, Carmelo; Pond, Dinel A.; Randolph, Linda M.; Rauen, Katherine A.; Rednam, Surya; Rutledge, S. Lane; Saletti, Veronica; Schaefer, G. Bradley; Schorry, Elizabeth K.; Scott, Daryl A.; Shugar, Andrea; Siqveland, Elizabeth; Starr, Lois J.; Syed, Ashraf; Trapane, Pamela L.; Ullrich, Nicole J.; Wakefield, Emily G.; Walsh, Laurence E.; Wangler, Michael F.; Zackai, Elaine; Claes, Kathleen B.M.; Wimmer, Katharina; van Minkelen, Rick; De Luca, Alessandro; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine M.

In: Genetics in Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Koczkowska, M, Callens, T, Gomes, A, Sharp, A, Chen, Y, Hicks, AD, Aylsworth, AS, Azizi, AA, Basel, DG, Bellus, G, Bird, LM, Blazo, MA, Burke, LW, Cannon, A, Collins, F, DeFilippo, C, Denayer, E, Digilio, MC, Dills, SK, Dosa, L, Greenwood, RS, Griffis, C, Gupta, P, Hachen, RK, Hernández-Chico, C, Janssens, S, Jones, KJ, Jordan, JT, Kannu, P, Korf, BR, Lewis, AM, Listernick, RH, Lonardo, F, Mahoney, MJ, Ojeda, MM, McDonald, MT, McDougall, C, Mendelsohn, N, Miller, DT, Mori, M, Oostenbrink, R, Perreault, S, Pierpont, ME, Piscopo, C, Pond, DA, Randolph, LM, Rauen, KA, Rednam, S, Rutledge, SL, Saletti, V, Schaefer, GB, Schorry, EK, Scott, DA, Shugar, A, Siqveland, E, Starr, LJ, Syed, A, Trapane, PL, Ullrich, NJ, Wakefield, EG, Walsh, LE, Wangler, MF, Zackai, E, Claes, KBM, Wimmer, K, van Minkelen, R, De Luca, A, Martin, Y, Legius, E & Messiaen, LM 2018, 'Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation', Genetics in Medicine. https://doi.org/10.1038/s41436-018-0269-0
Koczkowska, Magdalena ; Callens, Tom ; Gomes, Alicia ; Sharp, Angela ; Chen, Yunjia ; Hicks, Alesha D. ; Aylsworth, Arthur S. ; Azizi, Amedeo A. ; Basel, Donald G. ; Bellus, Gary ; Bird, Lynne M. ; Blazo, Maria A. ; Burke, Leah W. ; Cannon, Ashley ; Collins, Felicity ; DeFilippo, Colette ; Denayer, Ellen ; Digilio, Maria C. ; Dills, Shelley K. ; Dosa, Laura ; Greenwood, Robert S. ; Griffis, Cristin ; Gupta, Punita ; Hachen, Rachel K. ; Hernández-Chico, Concepción ; Janssens, Sandra ; Jones, Kristi J. ; Jordan, Justin T. ; Kannu, Peter ; Korf, Bruce R. ; Lewis, Andrea M. ; Listernick, Robert H. ; Lonardo, Fortunato ; Mahoney, Maurice J. ; Ojeda, Mayra Martinez ; McDonald, Marie T. ; McDougall, Carey ; Mendelsohn, Nancy ; Miller, David T. ; Mori, Mari ; Oostenbrink, Rianne ; Perreault, Sebastién ; Pierpont, Mary Ella ; Piscopo, Carmelo ; Pond, Dinel A. ; Randolph, Linda M. ; Rauen, Katherine A. ; Rednam, Surya ; Rutledge, S. Lane ; Saletti, Veronica ; Schaefer, G. Bradley ; Schorry, Elizabeth K. ; Scott, Daryl A. ; Shugar, Andrea ; Siqveland, Elizabeth ; Starr, Lois J. ; Syed, Ashraf ; Trapane, Pamela L. ; Ullrich, Nicole J. ; Wakefield, Emily G. ; Walsh, Laurence E. ; Wangler, Michael F. ; Zackai, Elaine ; Claes, Kathleen B.M. ; Wimmer, Katharina ; van Minkelen, Rick ; De Luca, Alessandro ; Martin, Yolanda ; Legius, Eric ; Messiaen, Ludwine M. / Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del) : an update of genotype–phenotype correlation. In: Genetics in Medicine. 2018.
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abstract = "Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8{\%} of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8{\%} had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.",
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TY - JOUR

T1 - Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del)

T2 - an update of genotype–phenotype correlation

AU - Koczkowska, Magdalena

AU - Callens, Tom

AU - Gomes, Alicia

AU - Sharp, Angela

AU - Chen, Yunjia

AU - Hicks, Alesha D.

AU - Aylsworth, Arthur S.

AU - Azizi, Amedeo A.

AU - Basel, Donald G.

AU - Bellus, Gary

AU - Bird, Lynne M.

AU - Blazo, Maria A.

AU - Burke, Leah W.

AU - Cannon, Ashley

AU - Collins, Felicity

AU - DeFilippo, Colette

AU - Denayer, Ellen

AU - Digilio, Maria C.

AU - Dills, Shelley K.

AU - Dosa, Laura

AU - Greenwood, Robert S.

AU - Griffis, Cristin

AU - Gupta, Punita

AU - Hachen, Rachel K.

AU - Hernández-Chico, Concepción

AU - Janssens, Sandra

AU - Jones, Kristi J.

AU - Jordan, Justin T.

AU - Kannu, Peter

AU - Korf, Bruce R.

AU - Lewis, Andrea M.

AU - Listernick, Robert H.

AU - Lonardo, Fortunato

AU - Mahoney, Maurice J.

AU - Ojeda, Mayra Martinez

AU - McDonald, Marie T.

AU - McDougall, Carey

AU - Mendelsohn, Nancy

AU - Miller, David T.

AU - Mori, Mari

AU - Oostenbrink, Rianne

AU - Perreault, Sebastién

AU - Pierpont, Mary Ella

AU - Piscopo, Carmelo

AU - Pond, Dinel A.

AU - Randolph, Linda M.

AU - Rauen, Katherine A.

AU - Rednam, Surya

AU - Rutledge, S. Lane

AU - Saletti, Veronica

AU - Schaefer, G. Bradley

AU - Schorry, Elizabeth K.

AU - Scott, Daryl A.

AU - Shugar, Andrea

AU - Siqveland, Elizabeth

AU - Starr, Lois J.

AU - Syed, Ashraf

AU - Trapane, Pamela L.

AU - Ullrich, Nicole J.

AU - Wakefield, Emily G.

AU - Walsh, Laurence E.

AU - Wangler, Michael F.

AU - Zackai, Elaine

AU - Claes, Kathleen B.M.

AU - Wimmer, Katharina

AU - van Minkelen, Rick

AU - De Luca, Alessandro

AU - Martin, Yolanda

AU - Legius, Eric

AU - Messiaen, Ludwine M.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

AB - Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

KW - genotype–phenotype correlation

KW - learning difficulties

KW - neurofibroma

KW - NF1

KW - p.Met992del

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