1. Genotype-phenotype correlation in NF1 : evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844–848
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Elizabeth Siqveland, Concepción Hernández-Chico, Jonathan Zonana, Melissa Crenshaw, Maurice J. Mahoney, Eric Legius, Helene Verhelst, Débora Romeo Bertola, Karen W. Gripp, Tom Callens, Jaishri O. Blakeley, Nicole J. Ullrich, Arelis Martir-Negron, Karol Rubin, Marica Eoli, Margaret R. Wallace, Jose Guevara-Campos, Karin Dahan, Zhenbin Chen, Patricia Galvin-Parton, Elaine H. Zackai, Isabelle Maystadt, Radhika Dhamija, Lane S. Rutledge, Meriel McEntagart, Rick van Minkelen, Geert Mortier, Meena Balasubramanian, La Donna Immken, Maria Daniela D'Agostino, Anne Destree, Alicia Gomes, Kenneth N. Rosenbaum, Rhonda L. Schonberg, Emma Burkitt-Wright, Meng-Chang Hsiao, Meena Upadhyaya, Sherrell Johnson, Meredith Seidel, Alessandro De Luca, Troy A. Becker, David T. Miller, Veronica Saletti, Bruce R. Korf, Shay Ben-Shachar, Carey McDougall, David W. Stockton, Magdalena Koczkowska, Kathleen Claes, Laura Russell, Ludwine Messiaen, D. Gareth Evans, Mitch Cunningham, Allison Schreiber, Scott R. Plotkin, Dinel A. Pond, Kristi J. Jones, Vickie Zurcher, Jaya K. George-Abraham, Alison Callaway, Beth Keena, Yunjia Chen, Neil A. Hanchard, Angela Sharp, Yoon Sim Yap, Karin Soares Gonçalves Cunha, Nancy J. Mendelsohn, Jenny Morton, Christopher P. Barnett, Yolanda Martin, Aaina Kochhar, Eva Trevisson, Jan Liebelt, John Pappas, Sandra Janssens, and Clinical Genetics
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0301 basic medicine ,Proband ,Male ,Cohort Studies ,codons 844–848 ,Medicine and Health Sciences ,Missense mutation ,CSRD ,Child ,Genetics (clinical) ,Neurofibromatosis type I ,Genetics ,education.field_of_study ,NEUROFIBROMATOSIS TYPE-I ,Neurofibromin 1 ,Genetic disorder ,Phenotype ,NERVE SHEATH TUMORS ,Female ,codons 844-848 ,Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,spinal NF ,Neurofibromatosis 1 ,VONRECKLINGHAUSEN NEUROFIBROMATOSIS ,Adolescent ,Genetic counseling ,Population ,Mutation, Missense ,NOONAN-SYNDROME ,Spinal neurofibromas ,genotype-phenotype correlation ,neurofibromatosis type 1 ,Article ,03 medical and health sciences ,Young Adult ,MPNST ,missense mutation ,NF1 ,plexiform neurofibroma ,medicine ,Humans ,Computer Simulation ,Amino Acid Sequence ,OPTIC PATHWAY GLIOMAS ,Neurofibromatosis ,education ,Codon ,Genetic Association Studies ,Demography ,SPINAL NEUROFIBROMATOSIS ,business.industry ,Biology and Life Sciences ,NATURAL-HISTORY ,SOUTH EAST WALES ,medicine.disease ,030104 developmental biology ,TYPE-1 NEUROFIBROMATOSIS ,Human medicine ,business ,PLEXIFORM NEUROFIBROMAS - Abstract
Neurofibromatosis type 1 (NF1), one of the most common genetic disorders with an estimated prevalence of 1:3000 live births, 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 an in-frame 1-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 patients (129 unrelated probands and 33 affected relatives) carrying 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). These recurrent missense mutations affect ~0.8% of unrelated NF1 mutation-positive probands in the UAB cohort. A substantial fraction of these patients presented with a severe phenotype, including plexiform and/or spinal neurofibromas, symptomatic optic pathway gliomas, malignant neoplasms or osseous lesions. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent compared with classic NF1 cohorts (both p
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- 2018
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