Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients.
Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients.
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全外显子组测序揭示范可尼贫血患者多个 FA 基因的伴随突变
DOI：
10.1186/1755-8794-7-24
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发表时间：
2014-05-15
影响因子：
2.7
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Chang L;Yuan W;Zeng H;Zhou Q;Wei W;Zhou J;Li M;Wang X;Xu M;Yang F;Yang Y;Cheng T;Zhu X
Fanconi贫血(FA)是一种罕见的遗传性遗传综合征，临床表现多种多样。目前已鉴定出15种FA基因亚型。传统的分组互补试验被广泛应用于FA患者的基因分型研究中，但这种方法可能导致FA患者的遗传信息不完整。对测序数据进行生物信息学分析，对外显子测序鉴定的FANC基因突变进行再测序。结果所有患者均检测到FANC基因纯合突变和复合杂合突变。FA亚型包括FANCA、FANCM和FANCD2。有趣的是，四名FA患者至少有两个FA基因存在多重突变，其中一些突变以前从未报道过。这些患者的临床表现有很大不同，对雄激素和泼尼松的治疗反应也不同。提示FA基因杂合性突变(S)也可能对FA患者或FA基因携带者产生不同的生物学和/或病理生理效应。有趣的是，当将患者的测序数据与其父母的测序数据进行比较时，我们未能发现DNA修复途径中涉及的基因中的新突变。结论我们的结果表明，中国FA患者和携带者的FANC基因突变率可能比传统认为的更高和更复杂。在FA患者及其家庭成员中检测15个FANC基因应成为常规的临床实践，以确定对单个患者的最佳治疗，为家庭提供咨询，并更好地了解FA的病理生理学。
BackgroundFanconi anemia (FA) is a rare inherited genetic syndrome with highly variable clinical manifestations. Fifteen genetic subtypes of FA have been identified. Traditional complementation tests for grouping studies have been used generally in FA patients and in stepwise methods to identify the FA type, which can result in incomplete genetic information from FA patients.MethodsWe diagnosed five pediatric patients with FA based on clinical manifestations, and we performed exome sequencing of peripheral blood specimens from these patients and their family members. The related sequencing data were then analyzed by bioinformatics, and the FANC gene mutations identified by exome sequencing were confirmed by PCR re-sequencing.ResultsHomozygous and compound heterozygous mutations of FANC genes were identified in all of the patients. The FA subtypes of the patients included FANCA, FANCM and FANCD2. Interestingly, four FA patients harbored multiple mutations in at least two FA genes, and some of these mutations have not been previously reported. These patients’ clinical manifestations were vastly different from each other, as were their treatment responses to androstanazol and prednisone. This finding suggests that heterozygous mutation(s) in FA genes could also have diverse biological and/or pathophysiological effects on FA patients or FA gene carriers. Interestingly, we were not able to identifyde novomutations in the genes implicated in DNA repair pathways when the sequencing data of patients were compared with those of their parents.ConclusionsOur results indicate that Chinese FA patients and carriers might have higher and more complex mutation rates in FANC genes than have been conventionally recognized. Testing of the fifteen FANC genes in FA patients and their family members should be a regular clinical practice to determine the optimal care for the individual patient, to counsel the family and to obtain a better understanding of FA pathophysiology.
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影响因子：
2.9
作者：
Gille JJ;Floor K;Kerkhoven L;Ameziane N;Joenje H;de Winter JP
通讯作者：
de Winter JP
影响因子：
11.4
作者：
Koptyra, M.;Stoklosa, T.;Hoser, G.;Glodkowska-Mrowka, E.;Seferynska, I.;Klejman, A.;Blasiak, J.;Skorski, T.
通讯作者：
Skorski, T.
影响因子：
30.8
作者：
Kim, Yonghwan;Lach, Francis P.;Desetty, Rohini;Hanenberg, Helmut;Auerbach, Arleen D.;Smogorzewska, Agata
通讯作者：
Smogorzewska, Agata
影响因子：
20.3
作者：
Kutler, DI;Singh, B;Auerbach, AD
通讯作者：
Auerbach, AD
影响因子：
30.8
作者：
Vaz, Fiona;Hanenberg, Helmut;Mathew, Christopher G.
通讯作者：
Mathew, Christopher G.