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

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
2025-08-09
DOI
https://doi.org/10.17615/jxbb-fv79
Primary Topic
Neurofibromatosis and Schwannoma Cases
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article
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article

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

Mari Mori, Donald Basel, Katharina Wimmer, Cristin Griffis et al.
Neurofibromatosis and Schwannoma Cases
article

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

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

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.

University of North Carolina at Chapel Hill (US)
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Neurofibromatosis and Schwannoma Cases
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