Telomerase insufficiency induced telomere erosion accumulation in successive generations in dyskeratosis congenita family
Telomerase insufficiency induced telomere erosion accumulation in successive generations in dyskeratosis congenita family
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DOI：
10.1002/mgg3.709
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发表时间：
2019-07-01
影响因子：
2
通讯作者：
Zeng, Sicong
中科院分区：
文献类型：
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作者：
He, Caixia;Jing, Shuang;Zeng, Sicong
背景先天性角化不良是一种罕见的遗传性骨髓衰竭综合征，与端粒功能障碍相关，具有高度的遗传异质性和多样的特征。目的研究一个年轻一代症状较重的DC家系的遗传病因，并探讨其与DC表型严重程度的关系。方法对先证者进行全外显子组测序，筛选候选致病基因。然后用瑞士模型软件预测蛋白质结构。对家系成员进行了端粒长度(TL)分析，并进行了大规模的人群对照。对再次妊娠父母的胎儿进行产前诊断(PND)。结果在先证者中发现了TERT(NM_198253.2)、C.1796G>；A(p.Arg599Gln)、c.2839T&Gt；C(p.Ser947Pro)和c.3346G&Gt；C(p.Glu1116Gln)的新杂合性突变。他的TL低于同龄人的第一个百分位数，通过PND也出现在患有表皮角化不良的胎儿身上。大规模群体和DC家族成员的TL数据表明，该家族在世代中积累了端粒侵蚀。结论我们的研究发现了3个临床病理TERT突变，提示端粒侵蚀可能在后代中积累，导致年轻一代DC的严重程度。
Background Dyskeratosis congenita (DC) is a rare heritable bone marrow failure syndrome that is associated with telomere dysfunction, and has high genetic heterogeneity and varied features. Objective This study aimed to identify the underlying genetic etiology of a DC family with more severe symptoms in the younger generation and to explore the relationship between the genetic causes and the severity of DC phenotype. Methods Whole-exome sequencing was performed on the proband to screen the candidate causative gene. The protein structure was then predicted by SWISS-MODEL software. Telomere length (TL) assay was performed on family members along with large-scale population controls. The prenatal diagnosis (PND) was performed on the fetus of parents with secondary pregnancy. Results Novel heterozygous mutations in TERT (NM_198253.2), c.1796G>A (p.Arg599Gln), c.2839T>C (p.Ser947Pro), and c.3346G>C (p.Glu1116Gln) were identified in the proband. His TL was below the first percentile of the peers, which also appeared on the fetus with epidermal dyskeratosis through PND. The TL data of large-scale population and members of the DC family implied the accumulation of telomere erosion in successive generations in this family. Conclusions Our study identified three clinical pathologic TERT mutations and implied that telomere erosion might be accumulated through successive generations, contributing to the severity of DC in the younger generation.