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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]

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