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 journalArticlepeer-review

20 Scopus citations


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 (US)
Pages (from-to)867-876
Number of pages10
JournalGenetics in Medicine
Issue number4
StatePublished - 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.


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

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