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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.

Publication ,  Journal Article
Koczkowska, M; Callens, T; Gomes, A; Sharp, A; Chen, Y; Hicks, AD; Aylsworth, AS; Azizi, AA; Basel, DG; Bellus, G; Bird, LM; Blazo, MA ...
Published in: Genet Med
April 2019

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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Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

April 2019

Volume

21

Issue

4

Start / End Page

867 / 876

Location

United States

Related Subject Headings

  • Young Adult
  • Sequence Deletion
  • Neurofibromin 1
  • Neurofibromatosis 1
  • Neurofibroma, Plexiform
  • Mutation, Missense
  • Male
  • Learning Disabilities
  • Infant
  • Humans
 

Citation

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Chicago
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Koczkowska, M., Callens, T., Gomes, A., Sharp, A., Chen, Y., Hicks, A. D., … 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. Genet Med, 21(4), 867–876. https://doi.org/10.1038/s41436-018-0269-0
Koczkowska, Magdalena, Tom Callens, Alicia Gomes, Angela Sharp, Yunjia Chen, Alesha D. Hicks, Arthur S. Aylsworth, 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.Genet Med 21, no. 4 (April 2019): 867–76. https://doi.org/10.1038/s41436-018-0269-0.
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. Genet Med. 2019 Apr;21(4):867–76.
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.Genet Med, vol. 21, no. 4, Apr. 2019, pp. 867–76. Pubmed, doi: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. 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. Genet Med. 2019 Apr;21(4):867–876.

Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

April 2019

Volume

21

Issue

4

Start / End Page

867 / 876

Location

United States

Related Subject Headings

  • Young Adult
  • Sequence Deletion
  • Neurofibromin 1
  • Neurofibromatosis 1
  • Neurofibroma, Plexiform
  • Mutation, Missense
  • Male
  • Learning Disabilities
  • Infant
  • Humans