%0 Journal Article
%T Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844¨C848
%A Aaina Kochhar
%A Alessandro De Luca
%A Alicia Gomes
%A Alison Callaway
%A Allison Schreiber
%A Angela Sharp
%A Anne Destr¨¦e
%A Arelis Martir-Negron
%A Beth A. Keena
%A Bruce R. Korf
%A Carey McDougall
%A Christopher P. Barnett
%A Concepcion Hern¨¢ndez-Chico
%A D. Gareth R. Evans
%A David T. Miller
%A David W. Stockton
%A Debora R. Bertola
%A Dinel Pond
%A Elaine Zackai
%A Elizabeth Siqveland
%A Emma M.M. Burkitt-Wright
%A Eric Legius
%A Eva Trevisson
%A Geert Mortier
%A Helene Verhelst
%A Isabelle Maystadt
%A Jaishri O. Blakeley
%A Jan Liebelt
%A Jaya K. George-Abraham
%A Jenny Morton
%A John Pappas
%A Jonathan Zonana
%A Jose Guevara-Campos
%A Karen W. Gripp
%A Karin Dahan
%A Karin S. Cunha
%A Karol Rubin
%A Kathleen Claes
%A Kenneth Rosenbaum
%A Kristi J. Jones
%A LaDonna Immken
%A Lane S. Rutledge
%A Laura Russell
%A Magdalena Koczkowska
%A Margaret R. Wallace
%A Maria D. D¡¯Agostino
%A Marica Eoli
%A Maurice J. Mahoney
%A Meena Balasubramanian
%A Meena Upadhyaya
%A Melissa Crenshaw
%A Meng-Chang Hsiao
%A Meredith Seidel
%A Meriel McEntagart
%A Mitch Cunningham
%A Nancy Mendelsohn
%A Neil A. Hanchard
%A Nicole J. Ullrich
%A Patricia Galvin-Parton
%A Radhika Dhamija
%A Rhonda Schonberg
%A Rick van Minkelen
%A Sandra Janssens
%A Scott R. Plotkin
%A Shay Ben-Shachar
%A Sherrell Johnson
%A Tom Callens
%A Troy A. Becker
%A Veronica Saletti
%A Vickie Zurcher
%A Yolanda Martin
%A Yoon-Sim Yap
%A Yunjia Chen
%A Zhenbin Chen
%J Archive of "American Journal of Human Genetics".
%D 2018
%R 10.1016/j.ajhg.2017.12.001
%X Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000¨C3,000, 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¡ªLeu844, Cys845, Ala846, Leu847, and Gly848¡ªlocated 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¨C848 exists and will be valuable in the management and genetic counseling of a significant number of individuals
%K neurofibromatosis type 1
%K NF1
%K genotype-phenotype correlation
%K missense mutation
%K codons 844¨C848
%K spinal NF
%K MPNST
%K plexiform neurofibroma
%K CSRD
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777934/