Dataset Information

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

ABSTRACT: Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ?0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.

SUBMITTER: Koczkowska M

PROVIDER: S-EPMC5777934 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

Koczkowska Magdalena M Chen Yunjia Y Callens Tom T Gomes Alicia A Sharp Angela A Johnson Sherrell S Hsiao Meng-Chang MC Chen Zhenbin Z Balasubramanian Meena M Barnett Christopher P CP Becker Troy A TA Ben-Shachar Shay S Bertola Debora R DR Blakeley Jaishri O JO Burkitt-Wright Emma M M EMM Callaway Alison A Crenshaw Melissa M Cunha Karin S KS Cunningham Mitch M D'Agostino Maria D MD Dahan Karin K De Luca Alessandro A Destrée Anne A Dhamija Radhika R Eoli Marica M Evans D Gareth R DGR Galvin-Parton Patricia P George-Abraham Jaya K JK Gripp Karen W KW Guevara-Campos Jose J Hanchard Neil A NA Hernández-Chico Concepcion C Immken LaDonna L Janssens Sandra S Jones Kristi J KJ Keena Beth A BA Kochhar Aaina A Liebelt Jan J Martir-Negron Arelis A Mahoney Maurice J MJ Maystadt Isabelle I McDougall Carey C McEntagart Meriel M Mendelsohn Nancy N Miller David T DT Mortier Geert G Morton Jenny J Pappas John J Plotkin Scott R SR Pond Dinel D Rosenbaum Kenneth K Rubin Karol K Russell Laura L Rutledge Lane S LS Saletti Veronica V Schonberg Rhonda R Schreiber Allison A Seidel Meredith M Siqveland Elizabeth E Stockton David W DW Trevisson Eva E Ullrich Nicole J NJ Upadhyaya Meena M van Minkelen Rick R Verhelst Helene H Wallace Margaret R MR Yap Yoon-Sim YS Zackai Elaine E Zonana Jonathan J Zurcher Vickie V Claes Kathleen K Martin Yolanda Y Korf Bruce R BR Legius Eric E Messiaen Ludwine M LM

American journal of human genetics 20171228 1

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, ...[more]

PMID: 29290338

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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

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

Publications

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

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