Candidate Pathogenic Genes Research Articles

Transcriptome profiling reveals insertional mutagenesis suppressed the expression of candidate pathogenicity genes in honeybee fungal pathogen, Ascosphaera apis

Chalkbrood disease is caused by Ascosphaera apis which severely affects honeybee brood. Spore inoculation experiments shown pathogenicity varies among different strains and mutants, however, the molecular mechanism of pathogenicity is unclear. We sequenced, assembled and annotated the transcriptomes of wild type (SPE1) and three mutants (SPE2, SPE3 and SPE4) with reduced pathogenicity that were constructed in our previous study. Illumina sequencing generated a total of 394,910,604 clean reads and de novo Trinity-based assembled into 12,989 unigenes, among these, 9,598 genes were successfully annotated to known proteins in UniProt database. A total of 172, 3,996, and 650 genes were up-regulated and 4,403, 2,845, and 3,016 genes were down-regulated between SPE2-SPE1, SPE3-SPE1, and SPE4-SPE1, respectively. Overall, several genes with a potential role in fungal pathogenicity were detected down-regulated in mutants including 100 hydrolytic enzymes, 117 transcriptional factors, and 47 cell wall related genes. KEGG pathway enrichment analysis reveals 216 genes involved in nine pathways were down-regulated in mutants compared to wild type. The down-regulation of more pathways involved in pathogenicity in SPE2 and SPE4 than SPE3 supports their lower pathogenicity during in-vitro bioassay experiment. Expression of 12 down-regulated genes in mutants was validated by quantitative real time PCR. This study provides valuable information on transcriptome variation caused by mutation for further functional validation of candidate pathogenicity genes in A. apis.

A novel hemizygous loss-of-function mutation in ADGRG2 causes male infertility with congenital bilateral absence of the vas deferens.

Cystic fibrosis transmembrane conductance regulator (CFTR) and adhesion G protein-coupled receptor G2 (ADGRG2) have been identified as the main pathogenic genes in congenital bilateral absence of the vas deferens (CBAVD), which is an important cause of obstructive azoospermia. This study aimed to identify the disease-causing gene in two brothers with CBAVD from a Chinese consanguineous family and reveal the intracytoplasmic sperm injection (ICSI) outcomes in these patients. Whole-exome sequencing and Sanger sequencing were used to identify the candidate pathogenic genes. Real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence were used to assess the expression of the mutant gene. Moreover, the ICSI results from both patients were retrospectively reviewed. A novel hemizygous loss-of-function mutation (c.G118T: p.Glu40*) in ADGRG2 was identified in both patients with CBAVD. This mutation is absent from the human genome databases and causes an early translational termination in the third exon of ADGRG2. Expression analyses showed that both the ADGRG2 mRNA and the corresponding protein were undetectable in the proximal epididymal tissue of ADGRG2-mutated patients. ADGRG2 expression was restricted to the apical membranes of non-ciliated epithelia in human efferent ducts, which was consistent with a previous report in mice. Both ADGRG2-mutated patients had normal spermatogenesis and had successful clinical outcomes following ICSI. Our study verifies the pathogenic role of ADGRG2 in X-linked CBAVD and broadens the spectrum of ADGRG2 mutations. In addition, we found positive ICSI outcomes in the two ADGRG2-mutated CBAVD patients.

Identification of potential candidate genes and pathways in atrioventricular nodal reentry tachycardia by whole-exome sequencing.

BackgroundAtrioventricular nodal reentry tachycardia (AVNRT) is the most common manifestation of paroxysmal supraventricular tachycardia (PSVT). Increasing data have indicated familial clustering and participation of genetic factors in AVNRT, and no pathogenic genes related to AVNRT have been reported.MethodsWhole‐exome sequencing (WES) was performed in 82 patients with AVNRT and 100 controls. Reference genes, genome‐wide association analysis, gene‐based collapsing, and pathway enrichment analysis were performed. A protein‐protein interaction (PPI) network was then established; WES database in the UK Biobank and one only genetic study of AVNRT in Denmark were used for external data validation.ResultsAmong 95 reference genes, 126 rare variants in 48 genes were identified in the cases (minor allele frequency < 0.001). Gene‐based collapsing analysis and pathway enrichment analysis revealed six functional pathways related to AVNRT as with neuronal system/neurotransmitter release cycles and ion channel/cardiac conduction among the top 30 enriched pathways, and then 36 candidate pathogenic genes were selected. By combining with PPI analysis, 10 candidate genes were identified, including RYR2, NOS1, SCN1A, CFTR, EPHB4, ROBO1, PRKAG2, MMP2, ASPH, and ABCC8. From the UK Biobank database, 18 genes from candidate genes including SCN1A, PRKAG2, NOS1, and CFTR had rare variants in arrhythmias, and the rare variants in PIK3CB, GAD2, and HIP1R were in patients with PSVT. Moreover, one rare variant of RYR2 (c.4652A > G, p.Asn1551Ser) in our study was also detected in the Danish study. Considering the gene functional roles and external data validation, the most likely candidate genes were SCN1A, PRKAG2, RYR2, CFTR, NOS1, PIK3CB, GAD2, and HIP1R.ConclusionThe preliminary results first revealed potential candidate genes such as SCN1A, PRKAG2, RYR2, CFTR, NOS1, PIK3CB, GAD2, and HIP1R, and the pathways mediated by these genes, including neuronal system/neurotransmitter release cycles or ion channels/cardiac conduction, might be involved in AVNRT.

Recent developments of plant pathogen effectors

In order to successfully invade and propagate in host plants, pathogens secrete effectors as invasive weapons. There are some differences and similarities among effectors of different pathogens. The systematic identification of plant pathogen effectors and the deep knowledge of the molecular interaction between the effectors and disease resistance genes, could provide practical significance in plant pathology and disease resistance breeding research. With the continuous development of sequencing technology, plant genomics and transcriptomics are increasingly utilized in plant disease resistance research. These sequencing results can be used to identify candidate pathogenic genes as well as plant disease resistance genes, and that would provide important information to understand the interaction between pathogens and plants. In this review, the function and characterization of effectors were reviewed and compared as well as the identification methods, pathogenic functions and disease resistance of plants were highlighted based on the research progress of pathogen effectors in plants in recent years. The application of effector in plant disease resistance and its research prospects are further prospected.

A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes.

There could be an overlap of monogenic diabetes and early-onset type 2 diabetes mellitus. Precise diagnosis of early-onset diabetes has proven valuable for understanding the mechanism of diabetes and selecting optimal therapy. The majority of maturity onset diabetes of the young (MODY) pathogenic genes in China is still unknown. In this study, a family with suspected MODY was enrolled. Whole-exome sequencing (WES) was used to analyze the variants of the proband. Variants were filtered according to their frequency, location, functional consequences, and bioinformatics software. Candidate pathogenic variants were validated by Sanger sequencing and tested for cosegregation in other members of the family and nonrelated healthy controls. KEGG (Kyoto Encyclopedia of Genes and Genomes) and PPI (protein-protein interaction) analysis were conducted using the DAVID (Database for Annotation, Visualization, and Integrated Discovery) and the STRING online analysis tools for the candidate pathogenic gene. A total of 123291 variants including 105344 SNPs and 17947 InDels were found in WES. A likely pathogenic rare missense heterozygous mutation in diabetes genes (c.2137C > T, p.His713Tyr in IRS1) was identified, which was a cosegregate in this family and not in nonrelated healthy controls. The position of the mutation in the aminoacid sequence of the gene is highly conserved among the species. 2 significantly enriched KEGG pathways were identified including bta04930, type II diabetes mellitus (GCK, INS, PDX1, ABCC8, and IRS1), and bta04910, insulin signaling pathway (GCK, INS, and IRS1). PPI analysis displayed that IRS1 interacts with 3 known pathogenic proteins including INS, KCNJ11, and GCK. We conclude that WES could be an initial option for genetic testing in patients with early-onset diabetes. IRS1 p.His713Tyr is implicated as a possible pathogenic mutation in monogenic diabetes, which might require further validation, and the precise molecular mechanism underlying the influence of IRS1 p.His713Tyr on the development of diabetes remains to be determined in the further prospective studies.

A candidate pathogenic gene, zinc finger gene 217 (ZNF217), may contribute to polycystic ovary syndrome through prostaglandin E2.

Polycystic ovary syndrome is a complex endocrine condition with chronic inflammation. Prostaglandin E2 (PGE2) is a proinflammatory factor with an increased expression in the serum of women with polycystic ovary syndrome. Zinc finger gene 217 (ZNF217) is known as a candidate gene for polycystic ovary syndrome. We aimed to investigate the relation between ZNF217 and PGE2 in polycystic ovary syndrome. We used a rat model of dehydroepiandrosterone-induced polycystic ovary syndrome and human granulosa cells both of women with polycystic ovary syndrome and of women without the syndrome to measure ZNF217 and other target gene expressions. In addition, we performed in vitro experiments with KGN human granulosa-like tumor cells to verify the molecular mechanisms. ZNF217 was decreased in the granulosa cells both of dehydroepiandrosterone-treated rats and of women with polycystic ovary syndrome. Cyclooxygenase 2, a key enzyme of PGE2 synthesis, was highly expressed in the granulosa cells of rats and women with the syndrome, and PGE2 concentration was increased in the follicular fluid. Furthermore, decreased ZNF217 expression was supposed to inhibit estradiol synthesis, which further promoted cyclooxygenase 2 and PGE2 synthesis. At the same time, PGE2 had an inhibitory effect on ZNF217 expression in a dose-dependent manner in KGN cells. Decreased ZNF217 expression in granulosa cells of women with polycystic ovary syndrome induced inflammation via PGE2, and PGE2 inhibited ZNF217 expression to establish a feedback loop. This mechanism might account for the pathogenesis of polycystic ovary syndrome.

TUBB1 mutation in children with congenital hypothyroidism and thyroid dysgenesis in Shandong, China

To study the types and characteristics of TUBB1 mutation in children with congenital hypothyroidism (CH) and thyroid dysgenesis (TD) in Shandong, China. Mutations of the whole coding region of the TUBB1 gene were analyzed for 289 children with CH and TD in Shandong. Whole-genome DNA was extracted from peripheral blood leukocytes. PCR multiplication was performed for the whole coding region of the TUBB1 gene. Sanger sequencing was performed for the PCR products, and a biological information analysis was performed. Among the 289 children with CH and TD, 4 (1.4%) were found to have a c.952C>T(p.R318W) heterozygous mutation in the TUBB1 gene, resulting in the change of tryptophan into arginine at codon 318 of TUBB1 protein. This mutation was evaluated as "potentially pathogenic" based on the classification criteria and guidelines for genetic variation by American College of Medical Genetics and Genomics. A novel mutation is detected in the exon of the TUBB1 gene in children with CH and TD in Shandong, suggesting that the TUBB1 gene may be a candidate pathogenic gene for CH children with TD.

Establishment and preliminary mechanism study of the zebrafish strain of KIAA0196: A candidate pathogenic gene for heart development

To explore the effects of KIAA0196 gene on cardiac development and the establishment of zebrafish strain. Methods: Peripheral blood and gDNA from patients were extracted. Copy number variation analysis and target sequencing were conducted to screen candidate genes. The KIAA0196 knockout zebrafish was generated by CRISPR/Cas9 to detect whether KIAA0196 deficiency could affect cardiac development. Finally, the wild-type and mutant zebrafish were anatomized and histologically stained to observe the phenotype of heart defects. Results: The KIAA0196 knockout zebrafish strain was successfully constructed using CRISPR/Cas9 technology. After 60 hours fertilization, microscopic examination of KIAA0196 knockout zebrafish (heterozygote + homozygote) showed pericardial effusion, cardiac compression and severely curly tail. Compared with wild-type zebrafish, the hearts of mutant KIAA0196 zebrafish had cardiac defects including smaller atrium and larger ventricle, and the myocardial cells were looser. Conclusion: KIAA0196 gene plays an important regulatory role in the development of heart. It might be a candidate gene for congenital heart disease.

Association of STAT3 gene polymorphism with susceptibility to asthma in children

Objective To study the relationship between STAT3 gene (rs2293152, rs957970) polymorphism and susceptibility to bronchial asthma in children, and to lay the foundation for search of the candidate pathogenic gene of asthma and early prevention of the disease. Methods One hundred and thirty hospitalized asthmatic children or out-patients with asthma at Affiliated Hospital of Southwest Medical University from September 2013 to September 2017 were selected as asthmatic group, and at the same time 145 healthy children were selected from the Affiliated Hospital of Southwest Medical University as the healthy control group.Apply sequence specific primers-polymerase chain reaction (SSP-PCR) was applied to detect susceptibility single nucleotide polymorphism (SNP) of STAT3 gene (rs2293152, rs9579700). The statistical differences in distribution between genotype and allele were analyzed between the asthma group and the healthy control group. Results The distribution frequency of CC genotype of rs2293152 in STAT3 gene was significantly higher in the asthmatic group (19.2%)than that in the healthy control group (9.0%) (χ2=6.065, P=0.014). C allele was significantly higher in asthmatic group (41.9% vs.33.8%) (χ2=3.861, P=0.049). There was no significant difference in the distribution of rs957970 in STAT3 gene between the asthma group and the healthy control group. Conclusions The SNP of rs2293152 in STAT3 gene is associated with susceptibility to asthma in children in South Sichuan.C allele may be the susceptible gene for childhood asthma, while the SNP of rs957970 in STAT3 gene has no significant correlation with childhood asthma in Southern Sichuan. Key words: STAT3 gene; Single nucleotide polymorphism; Asthma; Susceptibility; Child

Novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation in a consanguineous Chinese family with premature ovarian insufficiency

To explore the candidate pathogenic gene in a premature ovarian insufficiency (POI) proband from a consanguineous marriage and detect the potential effects of mutation on cellular energy metabolism. Genetic and functional studies. Reproductive medicine center. A patient with POI, from a consanguineous family, and her family members were recruited from the Reproductive Center of the First Affiliated Hospital of Anhui Medical University. Whole exome sequencing (WES) was performed for the proband. Variation revealed by WES sequencing was validated by Sanger sequencing in her family. Sequencing data were combined with those of other sporadic cases listed in public databases to identify the causative gene. Rare homozygous nonsynonymous variants were identified and included in subsequent analysis. Metabolic analyzes were performed using Seahorse XFe96 analyzers to measure oxygen consumption and then obtain further results of ATP production and extracellular acidification rate. The differences in energy metabolism measurements between wild type and mutation were analyzed and compared. A novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation (NM_020745: exon2: c.337G>C: p. G113R) was identified in the aminoacylation region using WES. The mutation was highly conserved among species and predicted to be disease causing. AARS2 encodes mitochondrial alanyl-tRNA synthetase, which attaches alanine onto tRNA-ala. AARS2 mutations were previously reported in female leukodystrophy patients with POI. In mitochondrial stress tests, the ATP productions of the mutation group (3.58 ± 0.46fmol/min/cell) was significantly lower than that of the wild type group (6.96 ± 1.56fmol/min/cell). This is the first report of a homozygous pathogenic AARS2 mutation in POI. This mutation may lead to incorrect aminoacylation of tRNA, affect mitochondrial translation, and cause oxidative phosphorylation defects, which may be responsible for POI.

Identification of Pathogenic Genes and Transcription Factors in Osteosarcoma.

Osteosarcoma (OS) is an aggressive malignant tumor of the bones. Our study intended to identify and analyze potential pathogenic genes and upstream regulators for OS. We performed an integrated analysis to identify candidate pathogenic genes of OS by using three Gene Expression Omnibus (GEO) databases (GSE66673, GSE49003 and GSE37552). GO and KEGG enrichment analysis were utilized to predict the functional annotation and potential pathways of differentially expressed genes (DEGs). The OS-specific transcriptional regulatory network was established to study the crucial transcriptional factors (TFs) which target the DEGs in OS. From the three GEO datasets, we identified 759 DEGs between metastasis OS samples and non-metastasis OS samples. After GO and KEGG analysis, 'cell adhesion' (FDR = 1.27E-08), 'protein binding' (FDR = 1.13E-22), 'cytoplasm' (FDR = 5.63E-32) and 'osteoclast differentiation' (FDR = 0.000992221) were significantly enriched pathways for DEGs. HSP90AA1 exhibited a highest degree (degree = 32) and was enriched in 'pathways in cancer' and 'signal transduction'. BMP6, regulated by Pax-6, was enriched in the 'TGF-beta signaling pathway'. We indicated that BMP6 may be downregulated by Pax-6 in the non-metastasis OS samples. The up-regulated HSP90AA1 and down-regulated BMP6 and 'pathways in cancer' and 'signal transduction' were deduced to be involved in the pathogenesis of OS. The identified biomarkers and biological process in OS may provide foundation for further study.

The Phenolyzer Suite: Prioritizing the Candidate Genes Involved in Microtia.

Microtia is a congenital malformation of the external ear. Great progress about the genetic of microtia has been made in recent years. This article was to prioritize the potential candidate pathogenic genes of microtia based on existing studies and reports, with the purpose of narrowing the range of following study scientifically and quickly. A computational tool called Phenolyzer (phenotype-based gene analyzer) was used to prioritize microtia genes. Microtia, as a query term, was input in the interface of Phenolyzer. After several steps, including disease match, gene query, gene score system, seed gene growth, and gene ranking, the final results about genetic information of microtia were provided. Then we tracked details of the top 10 genes ranked by Phenolyzer on the basis of previous reports. We detected 10 348 genes associated with microtia or related syndromes, and 78 genes of those genes belonged to seed genes. Every gene was given a score, and the gene with higher scores was more likely influence microtia. The top 10 ranked genes included HOXA2, CHD7, CDT1, ORC1, ORC4, ORC6, CDC6, MED12, TWIST1, and GLI3. Otherwise, four gene-gene interactions were displayed. This article prioritized candidate genes of microtia for the first time. High-throughput methods provide tens of thousands of single-nucleotide variants, indels, and structural variants, and only a handful are relevant to microtia or associated syndromes. Combine the ranked potential pathogenic genes list from Phenolyzer with the results of samples provided by high-throughput methods, and more precise research directions are presented.

Corrigendum: Identification of the CFTR c.1666A>G Mutation in Hereditary Inclusion Body Myopathy Using Next-Generation Sequencing Analysis.

[This corrects the article DOI: 10.3389/fnins.2018.00329.].

Identification of the CFTR c.1666A>G Mutation in Hereditary Inclusion Body Myopathy Using Next-Generation Sequencing Analysis.

Hereditary Inclusion Body Myopathy (HIBM) is a rare autosomal dominant or recessive adult onset muscle disease which affects one to three individuals per million worldwide. This disease is autosomal dominant or recessive and occurs in adulthood. Our previous study reported a new subtype of HIBM linked to the susceptibility locus at 7q22.1-31.1. The present study is aimed to identify the candidate gene responsible for the phenotype in HIBM pedigree. After multipoint linkage analysis, we performed targeted capture sequencing on 16 members and whole-exome sequencing (WES) on 5 members. Bioinformatics filtering was performed to prioritize the candidate pathogenic gene variants, which were further genotyped by Sanger sequencing. Our results showed that the highest peak of LOD score (4.70) was on chromosome 7q22.1-31.1.We identified 2 and 22 candidates using targeted capture sequencing and WES respectively, only one of which as CFTRc.1666A>G mutation was well cosegregated with the HIBM phenotype. Using transcriptome analysis, we did not detect the differences of CFTR's mRNA expression in the proband compared with healthy members. Due to low incidence of HIBM and there is no other pedigree to assess, mutation was detected in three patients with duchenne muscular dystrophyn (DMD) and five patients with limb-girdle muscular dystrophy (LGMD). And we found that the frequency of mutation detected in DMD and LGMD patients was higher than that of being expected in normal population. We suggested that the CFTRc.1666A>G may be a candidate marker which has strong genetic linkage with the causative gene in the HIBM family.

Asn391Thr Mutation of β-Myosin Heavy Chain in a Hypertrophic Cardiomyopathy Family.

The present study was performed to identify the genetic abnormalities in a family with familial hypertrophic cardiomyopathy.Peripheral blood samples were collected from 22 members of a Chinese family with hypertrophic cardiomyopathy and 307 healthy controls. A total of 26 candidate pathogenic genes were analyzed in the proband using targeted capture sequencing. Identified mutations were analyzed using Sanger sequencing in all family members and healthy controls.A missense mutation (c.1172A>C, p. Asn391Thr) in exon 12 of MYH7 was identified in eight family members, among which six of them were hypertrophic cardiomyopathy carriers. Three carriers presented with cardiac dysfunction. Four members of this pedigree died suddenly, three of whom were diagnosed with hypertrophic cardiomyopathy.From the results of this study, we concluded that the Asn391Thr mutation of MYH7 is a malignant mutation for HCM and that mutation carriers should get effective treatment to prevent sudden death.

Whole-exome sequencing reveals a rare interferon gamma receptor 1 mutation associated with myasthenia gravis.

Our study is aimed to explore the underlying genetic basis of myasthenia gravis. We collected a Chinese pedigree with myasthenia gravis, and whole-exome sequencing was performed on the two affected siblings and their parents. The candidate pathogenic gene was identified by bioinformatics filtering, which was further verified by Sanger sequencing. The homozygous mutation c.G40A (p.V14M) in interferon gamma receptor 1was identified. Moreover, the mutation was also detected in 3 cases of 44 sporadic myasthenia gravis patients. The p.V14M substitution in interferon gamma receptor 1 may affect the signal peptide function and the translocation on cell membrane, which could disrupt the binding of the ligand of interferon gamma and antibody production, contributing to myasthenia gravis susceptibility. We discovered that a rare variant c.G40A in interferon gamma receptor 1 potentially contributes to the myasthenia gravis pathogenesis. Further functional studies are needed to confirm the effect of the interferon gamma receptor 1 on the myasthenia gravis phenotype.

Atypical microdeletion in 22q11 deletion syndrome reveals new candidate causative genes

Rationale:22q11 deletion syndrome, the most common chromosomal microdeletion disease, is caused by megabase-sized deletions on chromosome 22q11.2. It is characterized by a wide spectrum of congenital anomalies in velopharyngeal and facial, cardiac, genitourinary, vertebroskeletal, respiratory, digestive, and central nervous systems. Phenotype–genotype studies have revealed several causative genes that regulate the development of the third and fourth pharyngeal arches in human. However, the exact pathogenesis of this syndrome remains unknown. Herein, we report a case of 22q11 deletion syndrome with an atypical microdeletion of 125 kb.Patient concerns:A 15-year-old Chinese girl presented with symptoms of facial dysmorphia, cardiac defects, velopharyngeal insufficiency, splenomegaly, immunodeficiency, and thrombocytopenia.Diagnoses:Microarray analysis revealed a 22q11.23 deletion of 125 kb (chromosome 22: 24276973–24402263), suggesting the diagnosis of 22q11 deletion syndrome. The haploinsufficient genes included GSTT2B, GSTT2, DDTL, DDT, GSTTP1, LOC391322, GSTT1, and GSTTP2.Interventions:The patient was administrated glucocorticoids and calcium supplements.Outcomes:No epistaxis or petechiae episode occurred during the follow-up; her platelet count ranged between 60 × 109 and 80 × 109/L.Lessons:Although none of the previous reported causative genes were affected in the patient, her clinical manifestations were typical of 22q11 deletion syndrome, apart from her progressive splenomegaly. This case indicated 8 new candidate pathogenic genes for 22q11 deletion syndrome. Given that the loss of these genes was sufficient to induce 22q11DS defects, whether these genes directly influence the pathogenesis of 22q11DS or through interactions with known hotspot mutations is worthy of research.

Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation

Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.

Predicting pathogenic genes for primary myelofibrosis based on a system‑network approach.

The aim of the present study was to predict pathogenic genes for primary myelofibrosis (PMF) using a system-network approach by combining protein-protein interaction (PPI) network and gene expression data with known pathogenic genes. PMF gene expression profiles, known pathogenic genes and protein-protein interactions were obtained. Using these data, differentially expressed genes (DEGs) were identified between PMF and normal conditions using significance analysis of microarrays, and seed genes were determined based on the intersection of known pathogenic genes and the PMF gene expression profile. A new network was constructed using the seed genes and their adjacent DEGs within the PPI network. Subsequently, a pathogenic network was extracted from the new network, and contained genes that interacted with at least two seed genes, and the candidate pathogenic genes were predicted based on the cohesion with seed genes. Cluster analysis was performed to mine the pathogenic modules from the pathogenic network, and functional analysis was performed to identify the putative biological processes of the candidate pathogenic genes. Results from the present study identified 845 DEGs between PMF and normal conditions, and 45 seed genes in PMF were screened. Subsequently, a pathogenic network comprising 103 nodes and 265 interactions was constructed, and 4 pathogenic modules (modules A-D) were mined from the pathogenic network. There were nine candidate pathogenic genes contained within Module A and four potential pathogenic genes, including E1A-binding protein p300, RAS-like proto-oncogene A, von Willebrand factor and RAF-1 proto-oncogene, serine/threonine kinase, were identified that may be involved in the same biological process with the seed genes. This study predicted 10 candidate pathogenic genes and several signaling pathways that may be related to the pathogenesis of PMF using a system-network approach. These predictions may shed light on the PMF pathogenesis and may provide guidelines for future experimental verification.

Identification of global transcriptome abnormalities and potential biomarkers in eutopic endometria of women with endometriosis: A preliminary study.

The etiology and pathophysiology of endometriosis remain unclear. The aim of the current study was to identify a candidate pathogenic gene, as well as potential biomarkers of endometriosis using messenger RNA (mRNA) sequencing (mRNA-seq). Twenty-three eutopic endometria from women with endometriosis and 20 endometria from control subjects were investigated. Eight eutopic endometria and five normal endometria were selected for mRNA-seq. Differentially expressed genes (DEGs) were identified and functional analysis was conducted. Validation of certain DEGs was performed in the remaining cases and control subjects by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 72 DEGs (66 upregulated and 6 downregulated) were identified in samples from women with endometriosis and compared with the control subjects. High DEGs included those involved in various functions, such as extracellular matrix (ECM) remodeling, angiogenesis, cell proliferation and differentiation. Enriched by these DEGs, 100 Gene Ontology terms were identified as significantly important, particularly ‘ECM’ and ‘endogenous stimulus’. Validation using RT-qPCR indicated that matrix metallopeptidase 11, dual specificity phosphatase 1, Fos proto-oncogeneand serpin family E member 1 were significantly upregulated and adenosine deaminase 2 was significantly downregulated in the eutopic endometrium of patients with endometriosis. The identified DEGs may be involved in the pathogenesis of endometriosis and may be potential biomarkers in the eutopic endometrium. The current study provides a comprehensive, but preliminary insight for elucidating the mechanisms of endometriosis, which require further in-depth studies for confirmation.