التفاصيل البيبلوغرافية
| العنوان: |
Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848. |
| المؤلفون: |
Koczkowska, Magdalena1, Chen, Yunjia1, Callens, Tom1, Gomes, Alicia1, Sharp, Angela1, Johnson, Sherrell1, Hsiao, Meng-Chang1, Chen, Zhenbin1, Balasubramanian, Meena2, Barnett, Christopher P.3, Becker, Troy A.4, Ben-Shachar, Shay5, Bertola, Debora R.6, Blakeley, Jaishri O.7, Burkitt-Wright, Emma M.M.8, Callaway, Alison9, Crenshaw, Melissa4, Cunha, Karin S.10, Cunningham, Mitch11, D’Agostino, Maria D.12 |
| المصدر: |
American Journal of Human Genetics. Jan2018, Vol. 102 Issue 1, p69-87. 19p. |
| مصطلحات موضوعية: |
*NEUROFIBROMATOSIS 1, *MISSENSE mutation, *GENETIC code, *STATISTICAL correlation, *CYSTEINE |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
Academic Search Index |
Full Text Finder