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 Dosa; Robert 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

doi:10.1038/s41436-018-0269-0

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 journal › Article › peer-review

69 Scopus citations

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 language	English (US)
Pages (from-to)	867-876
Number of pages	10
Journal	Genetics in Medicine
Volume	21
Issue number	4
DOIs	https://doi.org/10.1038/s41436-018-0269-0
State	Published - Apr 1 2019

Bibliographical note

Funding Information:
We thank the individuals and their families for participating in this study. This work was supported by the Children’s Tumor Foundation by the Isaac and Sadie Fuchs Genotype–Phenotype Study (to L.M.M.) and by internal funds from the Medical Genomics Laboratory at UAB. M.K. is also affiliated with the Department of Biology and Medical Genetics at the Medical University of Gdansk in Poland. We thank our collaborators: Gail Graham (Children’s Hospital of Eastern Ontario in Ottawa), Stephanie M. Morris (Washington University in St. Louis), Dmitriy M. Niyazov (Ochsner Clinic Foundation in New Orleans), Catherine Ward-Melver (Akron Children’s Hospital), Lawrence Wong (Kaiser Permanente South Bay Medical Center in Harbor City), Katie Farmer (Tallahassee Memorial HealthCare), Monisha Samanta Kisling (Children’s National Medical Center in Washington), and Taylor Warner (University of Iowa Hospitals and Clinics) for confirming the accuracy of clinical information originally provided for their individuals as well as Ender Karaca (UAB) for performing targeted NF1 testing for UAB-R1873 family.

Publisher Copyright:
© 2018, American College of Medical Genetics and Genomics.

Keywords

NF1
genotype–phenotype correlation
learning difficulties
neurofibroma
p.Met992del

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10.1038/s41436-018-0269-0

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Koczkowska, M., Callens, T., Gomes, A., Sharp, A., Chen, Y., Hicks, A. D., Aylsworth, A. S., Azizi, A. A., Basel, D. G., Bellus, G., Bird, L. M., Blazo, M. A., Burke, L. W., Cannon, A., Collins, F., DeFilippo, C., Denayer, E., Digilio, M. C., Dills, S. K., ... Messiaen, L. M. (2019). 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, 21(4), 867-876. https://doi.org/10.1038/s41436-018-0269-0

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 2019, '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, vol. 21, no. 4, pp. 867-876. https://doi.org/10.1038/s41436-018-0269-0

@article{e3fb10b3ece74266a2d4d8c700d0ba2e,

title = "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",

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.",

keywords = "NF1, genotype–phenotype correlation, learning difficulties, neurofibroma, p.Met992del",

author = "Magdalena Koczkowska and Tom Callens and Alicia Gomes and Angela Sharp and Yunjia Chen and Hicks, {Alesha D.} and Aylsworth, {Arthur S.} and Azizi, {Amedeo A.} and Basel, {Donald G.} and Gary Bellus and Bird, {Lynne M.} and Blazo, {Maria A.} and Burke, {Leah W.} and Ashley Cannon and Felicity Collins and Colette DeFilippo and Ellen Denayer and Digilio, {Maria C.} and Dills, {Shelley K.} and Laura Dosa and Greenwood, {Robert S.} and Cristin Griffis and Punita Gupta and Hachen, {Rachel K.} and Concepci{\'o}n Hern{\'a}ndez-Chico and Sandra Janssens and Jones, {Kristi J.} and Jordan, {Justin T.} and Peter Kannu and Korf, {Bruce R.} and Lewis, {Andrea M.} and Listernick, {Robert H.} and Fortunato Lonardo and Mahoney, {Maurice J.} and Ojeda, {Mayra Martinez} and McDonald, {Marie T.} and Carey McDougall and Nancy Mendelsohn and Miller, {David T.} and Mari Mori and Rianne Oostenbrink and Sebasti{\'e}n Perreault and Pierpont, {Mary Ella} and Carmelo Piscopo and Pond, {Dinel A.} and Randolph, {Linda M.} and Rauen, {Katherine A.} and Surya Rednam and Rutledge, {S. Lane} and Veronica Saletti and Schaefer, {G. Bradley} and Schorry, {Elizabeth K.} and Scott, {Daryl A.} and Andrea Shugar and Elizabeth Siqveland and Starr, {Lois J.} and Ashraf Syed and Trapane, {Pamela L.} and Ullrich, {Nicole J.} and Wakefield, {Emily G.} and Walsh, {Laurence E.} and Wangler, {Michael F.} and Elaine Zackai and Claes, {Kathleen B.M.} and Katharina Wimmer and {van Minkelen}, Rick and {De Luca}, Alessandro and Yolanda Martin and Eric Legius and Messiaen, {Ludwine M.}",

note = "Funding Information: We thank the individuals and their families for participating in this study. This work was supported by the Children{\textquoteright}s Tumor Foundation by the Isaac and Sadie Fuchs Genotype–Phenotype Study (to L.M.M.) and by internal funds from the Medical Genomics Laboratory at UAB. M.K. is also affiliated with the Department of Biology and Medical Genetics at the Medical University of Gdansk in Poland. We thank our collaborators: Gail Graham (Children{\textquoteright}s Hospital of Eastern Ontario in Ottawa), Stephanie M. Morris (Washington University in St. Louis), Dmitriy M. Niyazov (Ochsner Clinic Foundation in New Orleans), Catherine Ward-Melver (Akron Children{\textquoteright}s Hospital), Lawrence Wong (Kaiser Permanente South Bay Medical Center in Harbor City), Katie Farmer (Tallahassee Memorial HealthCare), Monisha Samanta Kisling (Children{\textquoteright}s National Medical Center in Washington), and Taylor Warner (University of Iowa Hospitals and Clinics) for confirming the accuracy of clinical information originally provided for their individuals as well as Ender Karaca (UAB) for performing targeted NF1 testing for UAB-R1873 family. Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

year = "2019",

month = apr,

day = "1",

doi = "10.1038/s41436-018-0269-0",

language = "English (US)",

volume = "21",

pages = "867--876",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "4",

}

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.

N1 - Funding Information: We thank the individuals and their families for participating in this study. This work was supported by the Children’s Tumor Foundation by the Isaac and Sadie Fuchs Genotype–Phenotype Study (to L.M.M.) and by internal funds from the Medical Genomics Laboratory at UAB. M.K. is also affiliated with the Department of Biology and Medical Genetics at the Medical University of Gdansk in Poland. We thank our collaborators: Gail Graham (Children’s Hospital of Eastern Ontario in Ottawa), Stephanie M. Morris (Washington University in St. Louis), Dmitriy M. Niyazov (Ochsner Clinic Foundation in New Orleans), Catherine Ward-Melver (Akron Children’s Hospital), Lawrence Wong (Kaiser Permanente South Bay Medical Center in Harbor City), Katie Farmer (Tallahassee Memorial HealthCare), Monisha Samanta Kisling (Children’s National Medical Center in Washington), and Taylor Warner (University of Iowa Hospitals and Clinics) for confirming the accuracy of clinical information originally provided for their individuals as well as Ender Karaca (UAB) for performing targeted NF1 testing for UAB-R1873 family. Publisher Copyright: © 2018, American College of Medical Genetics and Genomics.

PY - 2019/4/1

Y1 - 2019/4/1

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 - NF1

KW - genotype–phenotype correlation

KW - learning difficulties

KW - neurofibroma

KW - p.Met992del

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UR - http://www.scopus.com/inward/citedby.url?scp=85053443613&partnerID=8YFLogxK

U2 - 10.1038/s41436-018-0269-0

DO - 10.1038/s41436-018-0269-0

M3 - Article

C2 - 30190611

AN - SCOPUS:85053443613

SN - 1098-3600

VL - 21

SP - 867

EP - 876

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 4

ER -

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

Abstract

Bibliographical note

Keywords

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