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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

(2019) GENETICS IN MEDICINE. 21(4). p.867-876
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Organization
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, p.Met992del, genotype-phenotype correlation, neurofibroma, learning difficulties, OPTIC PATHWAY TUMORS, NERVE SHEATH TUMORS, SOUTH EAST WALES, VONRECKLINGHAUSEN NEUROFIBROMATOSIS, TYPE-1 NEUROFIBROMATOSIS, NOONAN SYNDROME, MUTATIONS, CHILDREN, ASSOCIATION, GUIDELINES

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MLA
Koczkowska, Magdalena et al. “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 (2019): 867–876. Print.
APA
Koczkowska, M., Callens, T., Gomes, A., Sharp, A., Chen, Y., Hicks, A. D., Aylsworth, A. S., et al. (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.
Chicago author-date
Koczkowska, Magdalena, Tom Callens, Alicia Gomes, Angela Sharp, Yunjia Chen, Alesha D Hicks, Arthur S Aylsworth, et al. 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.
Chicago author-date (all authors)
Koczkowska, Magdalena, 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 Claes, Katharina Wimmer, Rick van Minkelen, Alessandro De Luca, Yolanda Martin, Eric Legius, and Ludwine M Messiaen. 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.
Vancouver
1.
Koczkowska M, Callens T, Gomes A, Sharp A, Chen Y, Hicks AD, et al. 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. 2019;21(4):867–76.
IEEE
[1]
M. Koczkowska et al., “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, 2019.
@article{8582480,
  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.},
  author       = {Koczkowska, Magdalena and Callens, Tom and Gomes, Alicia and Sharp, Angela and Chen, Yunjia and Hicks, Alesha D and Aylsworth, Arthur S and Azizi, Amedeo A and Basel, Donald G and Bellus, Gary and Bird, Lynne M and Blazo, Maria A and Burke, Leah W and Cannon, Ashley and Collins, Felicity and DeFilippo, Colette and Denayer, Ellen and Digilio, Maria C and Dills, Shelley K and Dosa, Laura and Greenwood, Robert S and Griffis, Cristin and Gupta, Punita and Hachen, Rachel K and Hernández-Chico, Concepción and Janssens, Sandra and Jones, Kristi J. and Jordan, Justin T and Kannu, Peter and Korf, Bruce R and Lewis, Andrea M and Listernick, Robert H and Lonardo, Fortunato and Mahoney, Maurice J and Ojeda, Mayra Martinez and McDonald, Marie T and McDougall, Carey and Mendelsohn, Nancy and Miller, David T and Mori, Mari and Oostenbrink, Rianne and Perreault, Sebastién and Pierpont, Mary Ella and Piscopo, Carmelo and Pond, Dinel A and Randolph, Linda M and Rauen, Katherine A and Rednam, Surya and Rutledge, S Lane and Saletti, Veronica and Schaefer, G Bradley and Schorry, Elizabeth K and Scott, Daryl A and Shugar, Andrea and Siqveland, Elizabeth and Starr, Lois J and Syed, Ashraf and Trapane, Pamela L and Ullrich, Nicole J and Wakefield, Emily G and Walsh, Laurence E and Wangler, Michael F and Zackai, Elaine and Claes, Kathleen and Wimmer, Katharina and van Minkelen, Rick and De Luca, Alessandro and Martin, Yolanda and Legius, Eric and Messiaen, Ludwine M},
  issn         = {1098-3600},
  journal      = {GENETICS IN MEDICINE},
  keywords     = {NF1,p.Met992del,genotype-phenotype correlation,neurofibroma,learning difficulties,OPTIC PATHWAY TUMORS,NERVE SHEATH TUMORS,SOUTH EAST WALES,VONRECKLINGHAUSEN NEUROFIBROMATOSIS,TYPE-1 NEUROFIBROMATOSIS,NOONAN SYNDROME,MUTATIONS,CHILDREN,ASSOCIATION,GUIDELINES},
  language     = {eng},
  number       = {4},
  pages        = {867--876},
  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},
  url          = {http://dx.doi.org/10.1038/s41436-018-0269-0},
  volume       = {21},
  year         = {2019},
}

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