Identification of candidate genes and pathways in retinopathy of prematurity by whole exome sequencing of preterm infants enriched in phenotypic extremes

AbstractRetinopathy of prematurity (ROP) is a vasoproliferative retinal disease affecting premature infants. In addition to prematurity itself and oxygen treatment, genetic factors have been suggested to predispose to ROP. We aimed to identify potentially pathogenic genes and biological pathways associated with ROP by analyzing variants from whole exome sequencing (WES) data of premature infants. As part of a multicenter ROP cohort study, 100 non-Hispanic Caucasian preterm infants enriched in phenotypic extremes were subjected to WES. Gene-based testing was done on coding nonsynonymous variants. Genes showing enrichment of qualifying variants in severe ROP compared to mild or no ROP from gene-based tests with adjustment for gestational age and birth weight were selected for gene set enrichment analysis (GSEA). Mean BW of included infants with pre-plus, type-1 or type 2 ROP including aggressive posterior ROP (n = 58) and mild or no ROP (n = 42) were 744 g and 995 g, respectively. No single genes reached genome-wide significance that could account for a severe phenotype. GSEA identified two significantly associated pathways (smooth endoplasmic reticulum and vitamin C metabolism) after correction for multiple tests. WES of premature infants revealed potential pathways that may be important in the pathogenesis of ROP and in further genetic studies.

Download Full-text

99-Case Study of Sporadic Aortic Dissection by Whole Exome Sequencing Indicated Novel Disease-Associated Genes and Variants in Chinese Population

BioMed Research International ◽

10.1155/2020/7857043 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Zanxin Wang ◽

Xianmian Zhuang ◽

Bailang Chen ◽

Junmin Wen ◽

Fang Peng ◽

...

Keyword(s):

Correlation Analysis ◽

Aortic Dissection ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chinese Population ◽

Enrichment Analysis ◽

Copy Number Variations ◽

Nucleotide Polymorphisms ◽

Pathogenic Variants ◽

Whole Exome

Background. In this study, the whole exome sequencing in human aortic dissection, a highly lethal cardiovascular disease, was investigated to explore the aortic dissection-associated genes and variants in Chinese population. Methods. Whole exome sequencing was performed in 99 cases of aortic dissection. All single nucleotide polymorphisms (SNPs), insertions/deletions (InDels), and copy number variations (CNVs) were filtered to exclude the benign variants. Enrichment analysis and disease-gene correlation analysis were performed. Results. 3425873 SNPs, 685245 InDels, and 1177 CNVs were identified, and aortic dissection-associated SNPs, InDels, and CNVs were collected. After the disease correlation analysis, 20 candidate genes were identified. Part of these genes such as MYH11, FBN1, and ACTA2 were consistent with previous studies, while MLX, DAB2IP, EP300, ZFYVE9, PML, and PRKCD were newly identified as candidate aortic dissection-associated genes. Conclusion. The pathogenic and likely pathogenic variants in most of AD-associated genes (FBN1, MYH11, EFEMP2, TGFBR2, FBN2, COL3A1, and MYLK) were identified in our cohort study, and pathogenic CNVs involved in MYH11, COL family, and FBN were also identified which are not detectable by other NGS analysis. The correlation between MLX, DAB2IP, EP300, ZFYVE9, PML, PRKCD, and aortic dissection was identified, and EP300 may play a key role in AD.

Download Full-text

POLE mutations improve the prognosis of endometrial cancer via regulating cellular metabolism through AMF/AMFR signal transduction

BMC Medical Genetics ◽

10.1186/s12881-019-0936-2 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 2

Author(s):

Yiran Li ◽

Yiding Bian ◽

Kai Wang ◽

Xiao-Ping Wan

Keyword(s):

Endometrial Cancer ◽

Exome Sequencing ◽

Cancer Patients ◽

Whole Exome Sequencing ◽

Gene Set Enrichment Analysis ◽

Sequencing Data ◽

Exome Sequencing Data ◽

Favorable Prognosis ◽

Whole Exome ◽

Whole Exome Sequencing Data

Abstract Background The morbidity and mortality of endometrial tumors, a common type of malignant cancer in women, have increased in recent years. POLE encodes the DNA polymerase ε, which is responsible for the leading strand DNA replication. Somatic mutations of POLE have been acknowledged in numerous cancers, resulting in the accumulation of DNA errors, leading to ultra-mutated tumors. Mutations in the exonuclease domain of POLE have been reported to improve progression-free survival in endometrial cancer. However, the potential relationship and underlying mechanism between POLE mutations and the prognosis of endometrial cancer patients remains unclear. Methods The whole exome sequencing data, RNA sequencing data, and clinical information were obtained from the TCGA database and employed for the analyses in this study. The detailed mutational information was analyzed using whole exome sequencing data and the mutated genes were shown with OncoPlot. The survival curves and cox proportional hazards regression analysis were used to accessed patient prognosis, the association of clinical characteristics and prognosis. Differentially expressed genes were analyzed by the edgeR R/Bioconductor package, then the GSEA Pre-ranked tool was used for Gene Set Enrichment Analysis (GSEA) to estimate the function of genes. Expression values were clustered using hierarchical clustering with Euclidean distance and ward linkage by the dendextend R package. Results POLE mutational status was proven to be an independent prognostic factor for endometrial cancer patients. Patients with somatic POLE mutations presented a favorable prognosis. POLE mutations regulated glycolysis and cytokine secretion, affecting cell metabolism and immune response. Autocrine motility factor (AMF)/PGI and AMFR/gp78 exhibited higher expression levels in POLE mutant patients. The comprehensive high expressions of AMFR/gp78 and low expression of POLE were associated with the favorable prognosis of endometrial cancer patients. Conclusions This study showed the POLE mutations a vital factor in endometrial cancer patients, leading to a higher expression of AMF/PGI and AMFR/gp78. These results suggested comprehensive consideration of the POLE mutations, expression of AMF/PGI and AMFR/gp78 may provide a more feasible and effective approach for the treatment of endometrial cancer, which might improve the prognosis.

Download Full-text

Whole-Exome Sequencing Reveals Rare Germline Mutations in Patients With Hemifacial Microsomia

Frontiers in Genetics ◽

10.3389/fgene.2021.580761 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaojun Chen ◽

Fatao Liu ◽

Zin Mar Aung ◽

Yan Zhang ◽

Gang Chai

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

Enrichment Analysis ◽

Germline Mutations ◽

Pathway Enrichment Analysis ◽

Hemifacial Microsomia ◽

Congenital Disease ◽

Pathway Enrichment ◽

Whole Exome

Hemifacial microsomia (HFM) is a rare congenital disease characterized by a spectrum of craniomaxillofacial malformations, including unilateral hypoplasia of the mandible and surrounding structures. Genetic predisposition for HFM is evident but the causative genes have not been fully understood. Thus, in the present study, we used whole-exome sequencing to screen 52 patients with HFM for rare germline mutations. We revealed 3,341 rare germline mutations in this patient cohort, including those in 13 genes previously shown to be associated with HFM. Among these HFM-related genes, NID2 was most frequently mutated (in 3/52 patients). PED4DIP, which has not been previously associated with HFM, exhibited rare variants most frequently (in 7/52 patients). Pathway enrichment analysis of genes that were mutated in >2 patients predicted the “laminin interactions” pathway to be most significantly disrupted, predominantly by mutations in ITGB4, NID2, or LAMA5. In summary, this study is the first to identify rare germline mutations in HFM. The likely disruptions in the signaling pathways due to the mutations reported here may be considered potential causes of HFM.

Download Full-text

Prognostic Values of Nucleotide Polymorphism in ARDS: A Whole Exome Sequencing Association Study

10.21203/rs.3.rs-40246/v1 ◽

2020 ◽

Author(s):

Jing-Yuan Xu ◽

Ai-Ran Liu ◽

Zong-Sheng Wu ◽

Jian-Feng Xie ◽

Xiao-Xiao Qu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Genetic Locus ◽

Prospective Trial ◽

Enrichment Analysis ◽

Outcome Analysis ◽

Apache Ii Score ◽

Nucleotide Polymorphism ◽

Whole Exome

Abstract Background Genetic locus were identified associated with ARDS outcome. Our goal was to explore the associations between genetic variants and outcome of ARDS, and the prognostic values of nucleotide polymorphism in ARDS.Methods This was a single-center, prospective trial enrolling adult ARDS patients. After baseline data were collected, blood samples were drawn to perform whole exome sequencing, and single nucleotide polymorphism (SNP) / insertion-deletion to explore the quantitative and functional associations between genetic variants and ICU outcome. Then the lung injury burden (LIB), which was defined as the ratio of nonsynonymous SNP number per megabase of DNA, was used to evaluate its value in predicting outcome of ARDS. Results A total of 105 ARDS patients were enrolled in the study, including 70 survivors and 35 nonsurvivors. Based on the analysis of a total of 65542 nonsynonymous SNP, LIB in survivors was significantly higher than nonsurvivors [1892 (1848 - 1942) /MB versus 1864 (1829 - 1910) /MB, p = 0.018], while GO analysis showed that 60 functions were correlated with ARDS outcome, KEGG enrichment analysis showed that SNP/InDels were enriched in 13 pathways. Several new SNPs were found potentially associated with ARDS outcome. Analysis of LIB was used to determine its outcome predicting ability, the area under the ROC curve of which was only 0.6103, and increase to 0.712 when combined with APACHE II score. Conclusions Genetic variants are associated with ARDS outcome; however, their prognostic value still need to be verified by larger trials.Trial registration Clinicaltrials.gov NCT02644798. Registered 20 April 2015.

Download Full-text

Application Value of Whole Exome Sequencing in Screening and Identifying Pathogenic Genes of Hypopharyngeal Carcinoma

10.21203/rs.3.rs-605116/v1 ◽

2021 ◽

Author(s):

Jingwei Yao ◽

Yubo Ding ◽

Xiong Liu ◽

Jialu Huang ◽

Minghui Zhang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Enrichment Analysis ◽

Hypopharyngeal Cancer ◽

Hypopharyngeal Carcinoma ◽

Future Research ◽

Go Annotation ◽

Pathogenic Genes ◽

Whole Exome ◽

Tissue Specimens

Abstract Background: Whole-exome sequencing has been used in many cancer research, but it is rarely used in Hypopharyngeal carcinoma. In our research, we performed whole-exome sequencing of DNA from 10 tumor tissue specimens from patients with hypopharyngeal cancer rather than targeted sequencing of specific genes.Methods: Whole-exome sequencing in 10 patients with hypopharyngeal carcinoma was performed to identify single nucleotide variations (SNVs) and insertions and deletions (INDELs). American College of Medical Genetics and Genomics (ACMG) guidelines were used to evaluate the pathogenicity of the selected variants. Gene Ontology (GO) and pathway enrichment were used to analyze the function and effect of mutated genes. Protein protein interaction (PPI) was analyzed by string online software.Results: 8113 mutation sites in 5326 genes were identified after strict screening. MEGF8, ITPR1, DYSF, DNAH10, CUL7, MYH14, LRP1, ASTN1, TTN, ASH1L, MYH11, KMT2C were mutated in more than 6 patients. We identified 72 pathogenic or potentially pathogenic mutations in 53 genes according to the ACMG guidelines. GO annotation and KEGG enrichment analysis show the possible effect of these pathogenic genes on cancer. Conclusion: We identified novel mutations in patients with hypopharyngeal cancer, and provided a foundation for future research on the pathogenesis of hypopharyngeal carcinoma and targeted treatment of hypopharyngeal carcinoma.

Download Full-text