Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.
Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.
复制标题
NF1中的基因型 - 表型相关性：与影响NF1密码子844-848的错义突变有关的更严重表型的证据。
DOI：
10.1016/j.ajhg.2017.12.001
复制
发表时间：
2018-01-04
影响因子：
9.8
通讯作者：
Messiaen LM
中科院分区：
文献类型：
--
作者：
Koczkowska M;Chen Y;Callens T;Gomes A;Sharp A;Johnson S;Hsiao MC;Chen Z;Balasubramanian M;Barnett CP;Becker TA;Ben-Shachar S;Bertola DR;Blakeley JO;Burkitt-Wright EMM;Callaway A;Crenshaw M;Cunha KS;Cunningham M;D'Agostino MD;Dahan K;De Luca A;Destrée A;Dhamija R;Eoli M;Evans DGR;Galvin-Parton P;George-Abraham JK;Gripp KW;Guevara-Campos J;Hanchard NA;Hernández-Chico C;Immken L;Janssens S;Jones KJ;Keena BA;Kochhar A;Liebelt J;Martir-Negron A;Mahoney MJ;Maystadt I;McDougall C;McEntagart M;Mendelsohn N;Miller DT;Mortier G;Morton J;Pappas J;Plotkin SR;Pond D;Rosenbaum K;Rubin K;Russell L;Rutledge LS;Saletti V;Schonberg R;Schreiber A;Seidel M;Siqveland E;Stockton DW;Trevisson E;Ullrich NJ;Upadhyaya M;van Minkelen R;Verhelst H;Wallace MR;Yap YS;Zackai E;Zonana J;Zurcher V;Claes K;Martin Y;Korf BR;Legius E;Messiaen LM
1型神经纤维瘤病（NF1）是一种常见的遗传性疾病，其出生发病率为1:20 00 - 3,000，其特点是临床表现变化很大。迄今为止，仅报道了影响p.a arg1809和p.Met922del的单个氨基酸缺失的NF1错义突变的两个临床相关的基因内基因型-表型相关性。这两种变异都倾向于明显的轻度NF1表型，既没有外部可见的皮肤/丛状神经纤维瘤，也没有其他肿瘤。在这里，我们报告了162个个体（129个不相关的先证者和33个受影响的亲属）的一个结构错义突变杂合，该突变影响位于半胱氨酸-丝氨酸富结构域（CSRD）的五个相邻NF1密码子- leu844， Cys845, Ala846， Leu847和gly848中的一个。总的来说，这些复发性错义突变影响了阿拉巴马大学伯明翰分校（UAB）队列中不相关的NF1突变阳性先证约0.8%。与典型的nf1感染组相比，这些个体中主要的浅表丛状神经纤维瘤和症状性脊髓神经纤维瘤更为普遍（p < 0.0001）。近一半的个体有症状或无症状视神经胶质瘤和/或骨骼异常。此外，与一般nf1感染人群相比，该地区的变异似乎赋予了恶性肿瘤的高易感性（p = 0.0061）。我们的研究结果表明，这些NF1错义突变虽然位于gap相关结构域之外，但可能是严重表现的重要风险因素。在NF1区域844-848存在基因型-表型相关性，这将对大量个体的管理和遗传咨询有价值。
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.
登录
查看更多内容
影响因子：
4
作者：
HUSON, SM;COMPSTON, DAS;HARPER, PS
通讯作者：
HARPER, PS
影响因子：
9.8
作者：
Fahsold, R;Hoffmeyer, S;Nürnberg, P
通讯作者：
Nürnberg, P
影响因子：
2
作者：
Blazo, MA;Lewis, RA;Plon, SE
通讯作者：
Plon, SE
影响因子：
3.2
作者：
Crucis, Anne;Richer, Wilfrid;Bourdeaut, Franck
通讯作者：
Bourdeaut, Franck
影响因子：
4
作者：
Kluwe, L;Tatagiba, M;Mautner, VF
通讯作者：
Mautner, VF