Mutational Epidemiology of Congenital Fibrinogen Disorders
Mutational Epidemiology of Congenital Fibrinogen Disorders
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DOI：
10.1055/s-0038-1673685
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发表时间：
2018-11-01
影响因子：
6.7
通讯作者：
Neerman-Arbez, Marguerite
中科院分区：
文献类型：
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作者：
Casini, Alessandro;Blondon, Marc;Neerman-Arbez, Marguerite
背景：FGA、FGB或FGG的许多突变导致先天性纤维蛋白原疾病（CFDs），但其流行病学特征尚不清楚。本研究的目的是评估CFD的分子流行病学，并制定一个genotyping strategy.Methods：从266个无关的CFD患者基因型在我们的实验室和CFD开放存取数据库（n = 1,142）的遗传数据进行了评估。我们制定了一个逐步筛选策略的分子诊断CFD和前瞻性测试这一战略上连续32个CFD probands.Results：我们确定了345个突变等位基因的整体，187杂合子，63纯合子和16复合杂合子个体。无纤维蛋白原血症几乎总是由无效突变引起的（98.6%），主要是FGA（85%）。低纤维蛋白原血症主要由FGB或FGG错义突变引起（54.2%）。异常纤维蛋白原血症几乎总是由FGA和FGG的杂合错义突变引起的（99.3%）。热点突变在定量（33.1%）和定性纤维蛋白原疾病（71.1%）中普遍存在。我们实验室的突变簇与CFD开放存取数据库中报道的相似。所提出的逐步遗传筛查策略在CFD的开发和验证样本中均被证明是有效的：对FGA外显子2、4、5和FGG外显子8的筛查以及对FGA 11 kb缺失的搜索导致了约80%的突变等位基因的鉴定，其中包括15个新突变。所提出的逐步遗传筛选策略可以提供一种有效的方法来鉴定致病突变，分析最少数量的外显子。
Background: Numerous mutations in FGA, FGB or FGG lead to congenital fibrinogen disorders (CFDs), but their epidemiology is not well characterized. The aim of this study was to evaluate the molecular epidemiology of CFD and to develop a genotyping strategy.Methods: Genetic data from 266 unrelated CFD patients genotyped at our laboratory and from a CFD open access database (n = 1,142) were evaluated. We developed a step-wise screening strategy for the molecular diagnosis of CFD and prospectively tested this strategy on 32 consecutive CFD probands.Results: We identified 345 mutated alleles overall, among 187 heterozygous, 63 homozygous and 16 compound heterozygous individuals. Afibrinogenemia was almost always caused by null mutations (98.6%), mainly in FGA (85%). Hypofibrinogenemia was mainly caused by missense mutations of FGB or FGG (54.2%). Dysfibrinogenemia was almost always caused by heterozygous missense mutations (99.3%) in FGA and FGG. Hotspot mutations were prevalent among quantitative (33.1%) and qualitative fibrinogen disorders (71.1%). The mutational cluster at our laboratory was similar with that reported in the CFD open access database. The proposed step-wise genetic screening strategy proved efficient in both the development and validation samples for CFD: the screening of FGA exons 2, 4, 5 and FGG exon 8 and search for the 11 kb deletion of FGA led to the identification of approximately 80% of mutated alleles, including 15 new mutations.Conclusion: The described molecular epidemiology of CFD is complex. The proposed step-wise genetic screening strategy may provide an efficient way to identify causative mutations analysing a minimal number of exons.