Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• American journal of human genetics, 2018-01, Vol.102 (1), p.69-87

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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.