Targeted sequencing reveals complex, phenotype-correlated genotypes in cystic fibrosis.
Targeted sequencing reveals complex, phenotype-correlated genotypes in cystic fibrosis.
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DOI：
10.1186/s12920-018-0328-z
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发表时间：
2018-02-13
影响因子：
2.7
通讯作者：
Khafizov K
中科院分区：
文献类型：
--
作者：
Ivanov M;Matsvay A;Glazova O;Krasovskiy S;Usacheva M;Amelina E;Chernyak A;Ivanov M;Musienko S;Prodanov T;Kovalenko S;Baranova A;Khafizov K
囊性纤维化（CF）是最常见的危及生命的遗传性疾病之一。CFTR基因大约有2000个变异被鉴定出来，其中一些已知是致病的，并且CFTR2数据库已经详细描述了300个致病突变，这使得CFTR基因的分析与传统方法相比更加复杂。我们对89名p.Phe508del纯合子阴性的成年患者进行了下一代测序（NGS）。84例患者有完整的临床和人口统计信息。通过将MLPA与NGS结合，我们在所有CF患者中鉴定出致病等位基因。重要的是，在10%的病例中，标准的生物信息学管道在识别致病突变方面效率低下。在38例（45%）病例中观察到IV-V类突变，主要是胰腺充足性CF患者；其余患者为I-III类突变。糖尿病仅见于I-III类纯合突变的患者。我们发现12%的患者有两个以上的致病性CFTR突变杂合。2例患者观察到p.[Arg1070Gln， Ser466*]复合等位基因，与轻度肺阻塞相关（FVC 107和109%对67%，CI 95%: 63-72%； FEV 90和111%对47%，CI 95%: 37-48%）。首次报道了p.[Phe508del， Leu467Phe]复合体等位基因，在4例（5%）患者中观察到。与标准方法相比，NGS可以是一种更能获取信息的技术。结合其等效的诊断性能，因此可以在临床实践中实施，尽管仍然需要仔细验证。本文的在线版本（10.1186/s12920-018-0328-z）包含补充资料，仅供授权用户使用。
Cystic fibrosis (CF) is one of the most common life-threatening genetic disorders. Around 2000 variants in the CFTR gene have been identified, with some proportion known to be pathogenic and 300 disease-causing mutations have been characterized in detail by CFTR2 database, which complicates its analysis with conventional methods. We conducted next-generation sequencing (NGS) in a cohort of 89 adult patients negative for p.Phe508del homozygosity. Complete clinical and demographic information were available for 84 patients. By combining MLPA with NGS, we identified disease-causing alleles in all the CF patients. Importantly, in 10% of cases, standard bioinformatics pipelines were inefficient in identifying causative mutations. Class IV-V mutations were observed in 38 (45%) cases, predominantly ones with pancreatic sufficient CF disease; rest of the patients had Class I-III mutations. Diabetes was seen only in patients homozygous for class I-III mutations. We found that 12% of the patients were heterozygous for more than two pathogenic CFTR mutations. Two patients were observed with p.[Arg1070Gln, Ser466*] complex allele which was associated with milder pulmonary obstructions (FVC 107 and 109% versus 67%, CI 95%: 63-72%; FEV 90 and 111% versus 47%, CI 95%: 37-48%). For the first time p.[Phe508del, Leu467Phe] complex allele was reported, observed in four patients (5%). NGS can be a more information-gaining technology compared to standard methods. Combined with its equivalent diagnostic performance, it can therefore be implemented in the clinical practice, although careful validation is still required. The online version of this article (10.1186/s12920-018-0328-z) contains supplementary material, which is available to authorized users.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Hamdaoui, Nabila;Baudoin-Legros, Maryvonne;Planelles, Gabrielle
通讯作者：
Planelles, Gabrielle
影响因子：
5.2
作者：
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通讯作者：
Cabet, Faiza
影响因子：
4.4
作者：
Gnad F;Baucom A;Mukhyala K;Manning G;Zhang Z
通讯作者：
Zhang Z
影响因子：
5.8
作者：
Choi, Yongwook;Chan, Agnes P.
通讯作者：
Chan, Agnes P.