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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.

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.

SUBMITTER: Koczkowska M

PROVIDER: S-EPMC6752285 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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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.

Koczkowska Magdalena M Callens Tom T Gomes Alicia A Sharp Angela A Chen Yunjia Y Hicks Alesha D AD Aylsworth Arthur S AS Azizi Amedeo A AA Basel Donald G DG Bellus Gary G Bird Lynne M LM Blazo Maria A MA Burke Leah W LW Cannon Ashley A Collins Felicity F DeFilippo Colette C Denayer Ellen E Digilio Maria C MC Dills Shelley K SK Dosa Laura L Greenwood Robert S RS Griffis Cristin C Gupta Punita P Hachen Rachel K RK Hernández-Chico Concepción C Janssens Sandra S Jones Kristi J KJ Jordan Justin T JT Kannu Peter P Korf Bruce R BR Lewis Andrea M AM Listernick Robert H RH Lonardo Fortunato F Mahoney Maurice J MJ Ojeda Mayra Martinez MM McDonald Marie T MT McDougall Carey C Mendelsohn Nancy N Miller David T DT Mori Mari M Oostenbrink Rianne R Perreault Sebastién S Pierpont Mary Ella ME Piscopo Carmelo C Pond Dinel A DA Randolph Linda M LM Rauen Katherine A KA Rednam Surya S Rutledge S Lane SL Saletti Veronica V Schaefer G Bradley GB Schorry Elizabeth K EK Scott Daryl A DA Shugar Andrea A Siqveland Elizabeth E Starr Lois J LJ Syed Ashraf A Trapane Pamela L PL Ullrich Nicole J NJ Wakefield Emily G EG Walsh Laurence E LE Wangler Michael F MF Zackai Elaine E Claes Kathleen B M KBM Wimmer Katharina K van Minkelen Rick R De Luca Alessandro A Martin Yolanda Y Legius Eric E Messiaen Ludwine M LM

Genetics in medicine : official journal of the American College of Medical Genetics 20180907 4

<h4>Purpose</h4>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.<h4>Methods</h4>A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathoge ...[more]

PMID: 30190611

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Project description:Neurofibromatosis type-1 (NF1) patients suffer from cutaneous and subcutaneous neurofibromas (CNF) and large plexiform neurofibromas (PNF). Whole gene deletions of the NF1 gene can cause a more severe phenotype compared to smaller intragenic changes. Two distinct groups of NF1 whole gene deletions are type-1 deletions and atypical deletions. Our aim was to assess volumes and averaged annual growth-rates of CNF and PNF in patients with NF1 whole gene deletions and to compare these with NF1 patients without large deletions of the NF1 gene. We retrospectively evaluated 140 whole-body MR examinations of 38 patients with NF1 whole gene deletions (type-1 group: n = 27/atypical group n = 11) and an age- and sex matched collective of 38 NF1-patients. Age-dependent subgroups were created (0-18 vs >18 years). Sixty-four patients received follow-up MRI examinations (NF1whole gene deletion n = 32/control group n = 32). Whole-body tumor-volumes were semi-automatically assessed (MedX, V3.42). Tumor volumes and averaged annual growth-rates were compared. Median tumor-burden was significantly higher in the type-1 group (418ml; IQR 77 - 950ml, p = 0.012) but not in the atypical group (356ml;IQR 140-1190ml, p = 0.099) when compared to the controls (49ml; IQR 11-691ml). Averaged annual growth rates were significantly higher in both the type-1 group (14%/year; IQR 45-36%/year, p = 0.004) and atypical group (11%/year; IQR 5-23%/year, p = 0.014) compared to the controls (4%/year; IQR1-8%/year). Averaged annual growth rates were significantly higher in pediatric patients with type-1 deletions (21%/year) compared with adult patients (8%/year, p = 0.014) and also compared with pediatric patients without large deletions of the NF1 gene (3.3%/year, p = 0.0015). NF1 whole gene deletions cause a more severe phenotype of NF1 with higher tumor burden and higher growth-rates compared to NF1 patients without large deletions of the NF1 gene. In particular, pediatric patients with type-1 deletions display a pronounced tumor growth.

Dataset Information

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.

Publications

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.

Similar Datasets

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