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Exome sequencing greatly expedites the progressive research of Mendelian diseases

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《医学前沿（英文）》 2014年第8卷第1期页码 42-57 doi: 10.1007/s11684-014-0303-9

摘要：

The advent of whole-exome sequencing (WES) has facilitated the discovery of rare structure and functional genetic variants. Combining exome sequencing with linkage studies is one of the most efficient strategies in searching disease genes for Mendelian diseases. WES has achieved great success in the past three years for Mendelian disease genetics and has identified over 150 new Mendelian disease genes. We illustrate the workflow of exome capture and sequencing to highlight the advantages of WES. We also indicate the progress and limitations of WES that can potentially result in failure to identify disease-causing mutations in part of patients. With an affordable cost, WES is expected to become the most commonly used tool for Mendelian disease gene identification. The variants detected cumulatively from previous WES studies will be widely used in future clinical services.

关键词： genetics whole-exome sequencing Mendelian disease disease gene

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Clinical characterization and diagnosis of cystic fibrosis through exome sequencing in Chinese infants

Liru Qiu, Fengjie Yang, Yonghua He, Huiqing Yuan, Jianhua Zhou

《医学前沿（英文）》 2018年第12卷第5期页码 550-558 doi: 10.1007/s11684-017-0567-y

摘要：

Cystic fibrosis (CF) is a fatal autosomal-recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by recurrent pulmonary infection with obstructive pulmonary disease. CF is common in the Caucasian population but is rare in the Chinese population. The symptoms of early-stage CF are often untypical and may sometimes manifest as Bartter syndrome (BS)-like hypokalemic alkalosis. Therefore, the ability of doctors to differentiate CF from BS-like hypokalemic alkalosis in Chinese infants is a great challenge in the timely and accurate diagnosis of CF. In China, sporadic CF has not been diagnosed in children younger than three years of age to date. Three infants, who were initially admitted to our hospital over the period of June 2013 to September 2014 with BS-like hypokalemic alkalosis, were diagnosed with CF through exome sequencing and sweat chloride measurement. The compound heterozygous mutations of the CFTR gene were detected in two infants, and a homozygous missense mutation was found in one infant. Among the six identified mutations, two are novel point mutations (c.1526G>C and c.3062C>T) that are possibly pathogenic. The three infants are the youngest Chinese patients to have been diagnosed with sporadic CF at a very early stage. Follow-up examination showed that all of the cases remained symptom-free after early intervention, indicating the potential benefit of very early diagnosis and timely intervention in children with CF. Our results demonstrate the necessity of distinguishing CF from BS in Chinese infants with hypokalemic alkalosis and the significant diagnostic value of powerful exome sequencing for rare genetic diseases. Furthermore, our findings expand the CFTR mutation spectrum associated with CF.

关键词： cystic fibrosis pseudo-Bartter syndrome hypokalemic alkalosis CFTR gene mutations infants diagnosis

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Exploring the cancer genome in the era of next-generation sequencing

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《医学前沿（英文）》 2012年第6卷第1期页码 48-55 doi: 10.1007/s11684-012-0182-x

摘要：

The emergence of next-generation sequencing technologies has led to dramatic advances in cancer genome studies. The increased efficiency and resolution of next-generation sequencing greatly facilitate the detection of genetic, genomic, and epigenomic alterations, such as single nucleotide mutations, small insertions and deletions, chromosomal rearrangements, copy number variations, and DNA methylation. Comprehensive analysis of cancer genomes through approaches of whole genome, exome, and transcriptome sequencing has significantly improved the understanding of cancer biology, diagnosis, and therapy. The present study briefly reviews the recent pioneering studies on cancer genome sequencing and provides an unprecedented insight into the landscape of genomic alterations in human sporadic cancers.

关键词： next-generation sequencing cancer genome whole genome sequencing exome transcriptome

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Identification of variants associated with sporadic thoracic aortic dissection: a case--control study

《医学前沿（英文）》 2021年第15卷第3期页码 438-447 doi: 10.1007/s11684-020-0826-1

摘要： Thoracic aortic dissection (TAD) without familial clustering or syndromic features is known as sporadic TAD (STAD). So far, the genetic basis of STAD remains unknown. Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population (N = 637). After population structure and genetic relationship and ancestry analyses, we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD. We found that COL3A1 was significantly relevant to STAD (P = 7.35 × 10⁻⁶) after 10 000 times permutation test (P = 2.49 × 10⁻³). Moreover, another independent cohort, including 423 cases and 734 non-STAD subjects (N = 1157), replicated our results (P = 0.021). Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues, and its expression was related to the extracellular matrix (ECM) pathway. Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway. We wanted to expand the knowledge of the genetic basis and pathology of STAD, which may further help in providing better genetic counseling to the patients.

关键词： sporadic thoracic aortic dissection exome sequencing gene COL3A1 case–control study extracellular matrix

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A novel variant in the gene in a large Chinese family with a unique phenotype of Clouston syndrome

《医学前沿（英文）》 2023年第17卷第2期页码 330-338 doi: 10.1007/s11684-022-0933-2

摘要： Clouston syndrome (OMIM #129500), also known as hidrotic ectodermal dysplasia type 2, is a rare autosomal dominant skin disorder. To date, four mutations in the GJB6 gene, G11R, V37E, A88V, and D50N, have been confirmed to cause this condition. In previous studies, the focus has been mainly on gene sequencing, and there has been a lack of research on clinical manifestations and pathogenesis. To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease, we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree. Detailed clinical examination included histopathology, hair microscopy, and scanning electron microscopy. We found a novel heterozygous missense variant (c.134G>C:p.G45A) for Clouston syndrome. We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients’ hair under scanning electron microscopy. Our data reveal that a novel variant (c.134G>C:p.G45A) plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.

关键词： Clouston syndrome whole exome sequencing GJB6 gene novel variant unique phenotype

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多囊卵巢综合征无排卵的胰岛素信号和雄激素合成的新遗传风险和代谢特征 Article

吴效科, 黄志超, 曹义娟, 李建, 李志强, 马红丽, 高敬书, 常惠, 张多加, 丛晶, 王宇, 吴奇, Xiaoxiao Han, Pui Wah Jacqueline Chung, Yiran Li, Xu Zheng, Lingxi Chen, Lin Zeng, Astrid Borchert, Hartmut Kuhn, Zi-Jiang Chen, Ernest Hung Yu Ng, Elisabet Stener-Victorin, 张和平, Richard S. Legro, Ben Willem J. Mol, 师咏勇

《工程（英文）》 2023年第23卷第4期页码 103-111 doi: 10.1016/j.eng.2022.08.013

摘要：

促排卵是多囊卵巢综合征（PCOS）不孕症的一线治疗方案。卵巢对促排卵治疗的排卵应答差被认为与胰岛素抵抗和高雄激素血症相关。在一个包含1000名PCOS不孕妇女（PCOSAct）的前瞻性队列中，我们开展了一项全外显子联合靶向单核苷酸多态性（SNP）测序以及代谢组学研究。在全基因组水平找出与无排卵显著相关的常见变异和罕见突变，并通过机器学习算法构建排卵预测模型。研究发现，ZNF438基因中标记为rs2994652 (p=2.47×10^–8)的常见变异和REC114基因中的一个罕见功能突变（rs182542888，p=5.79×10^–6）与促排卵治疗失败显著相关。携带rs2994652 A等位基因和REC114 p.Val101Leu (rs182542888)的PCOS不孕妇女进行促排卵治疗的总排卵率更低（分别为：比值比（OR）=1.96，95% 置信区间（CI）[1.55~2.49]；OR=11.52，95% CI [3.08~43.05]），出现排卵的间隔时间更长（平均56.7天vs.49.0天，p<0.001；78.1天vs.68.6天，p=0.014）。对于rs2994652突变者，L-苯丙氨酸水平升高并与胰岛素抵抗稳态模型（HOMA-IR）指数（r=0.22, p=0.05）和空腹血糖（r=0.33, p=0.003）呈正相关；对于rs182542888突变者，花生四烯酸代谢产物水平下降并与升高的抗苗勒管激素（r=－0.51, p=0.01）和总睾酮（r=－0.71, p=0.02）呈负相关。整合基因变异位点、代谢产物及临床特征的联合预测模型可提高对排卵的预测能力[曲线下面积（AUC）=76.7%]。ZNF438基因的一个常见变异和REC114基因的一个罕见功能突变，以及与二者相关的苯丙氨酸和花生四烯酸代谢物改变，与PCOS女性不孕症的促排卵治疗失败相关。