Global Medical Genetics最新文献

This communication concerns a crucial query in immunology, that is, the dimension of an epitope. The issue has essential implications in vaccine formulations.

Introduction   CEP152 encodes protein Cep152, which associates with centrosome function. The lack of Cep152 can cause centrosome duplication to fail. CEP152 mutates, causing several diseases such as Seckel syndrome-5 and primary microencephaly-9. Methods  In this study, we reported a patient diagnosed with epilepsy in Tianjin Children's Hospital. We performed clinical examination and laboratory test, and whole-exome sequencing was performed for the proband's and his parents' peripheral blood. The suspected compound-heterozygous variant in the CEP152 gene was verified by Sanger sequencing and quantitative real-time polymerase chain reaction technology. Results  We discovered three variants-two of them from CEP152 and one from HPD . The result showed the variants in CEP152 only. The patient presented with seizures frequently. Sanger sequencing showed two novel variants in CEP152 are in exon26 (NM_014985.3 c.3968C > A p.Ser1323*) and in exon16 (NM_014985.3 c.2034_2036del p.Tyr678*). Conclusions  We reported a novel compound-heterozygous variant in the CEP152 gene in this study. Most of the phenotypes are Seckel syndrome and primary microencephaly, and the novel variant may cause an atypical phenotype that is epilepsy.

Background  Aminoacyl-tRNA synthetases (ARSs) are evolutionarily conserved enzymes that ensure the accuracy of the translation process. Isoleucyl-tRNA synthetase 2 ( IARS2 ) gene is a type of ARS that encodes mitochondrial isoleucine-tRNA synthetase. Pathogenic variants in the IARS2 gene are associated with mitochondrial disease which involves several patients presenting broad clinical phenotypes. These clinical phenotypes include West syndrome, Leigh syndrome, and Cataract, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia syndrome. Only 29 cases have been reported worldwide. The patient manifested recurrent convulsions, and specific clinical manifestations included electrolyte disorders and recurrent infections. Methods  Whole-exome sequencing was performed on the child with West syndrome. Three-dimensional structure reconstruction and thermodynamic stability prediction were performed to further analyze the relationship between variation and phenotype. Conclusion  This study further expands the clinical spectrum of IARS2 pathogenic variants. The case summaries help raise clinical awareness of IARS2 -associated disease and reduce misdiagnosis. Result  In this report, a 13-month-old girl was diagnosed with West syndrome and Leigh syndrome for 7 months. Compound heterozygous variants in the IARS2 gene (NM_018060.4), c.2450G>A (Arg817His) and copy number variation (NC_000001. 11: g. (220267549_220284289) del), were detected by WES. This study further expands the clinical spectrum of IARS2 pathogenic variants. The case summaries help raise clinical awareness of IARS2-associated disease and reduce misdiagnosis.

Background  Variants of ubiquitin-specific protease 7 ( USP7 ) gene in humans are associated with a neurodevelopmental disorder-Hao-Fountain syndrome, its core symptoms including developmental delay, intellectual disability, and speech delay. Other variable symptoms can affect multiple systems. In present study, we report two patients with core features from two unrelated consanguineous families originating from the Tianjin Children's Hospital. Methods and Results  Genomic DNA was extracted from the peripheral blood samples collected from the probands with their family members and whole-exome sequencing (WES) was used to detect the pathogenic genes in the probands. Suspected variants were subsequently validated by Sanger sequencing. In family 1, WES revealed that the proband carried the de novo variant c.2697A > C (p.Leu899Phe) in USP7 (NM_003470.3). In family 2, WES identified the variant c.3305A > C (p.Asn1102Thr) in USP7 (NM_003470.3) from the proband. Conclusion  We reported two cases of Hao-Fountain syndrome caused by novel USP7 variants. In addition, we report the first case of mosaicism with a USP7 variant in Chinese family. Our findings demonstrate the importance of WES in diagnosis of genetic diseases and expands the USP7 variants spectrum in Hao-Fountain syndrome. Moreover, we summarize the cases caused by USP7 variants in the literature. Our study can provide a vital reference for the diagnosis of future cases.

Dementia is a syndrome that can cause a number of progressive illnesses that affect memory, thinking, and ability to perform everyday tasks. Alzheimer's disease (AD) is the most common cause of dementia and represents a major public health problem. AD is a progressive disease, where in early stages there is mild memory loss and in late-stage patient loses the ability to carry on a conversation. AD (for which there is no exact cause and cure known so far) is the sixth leading cause of deaths in the United States. Every 68 second someone develops AD. This study focuses on protein structure modeling of genes presenilin 1 and 2 ( PSEN1 and PSEN2 ) and their mutated forms (Asn141Tyr found in Chinese family, Gly34Ser identified in a Japanese patient, and Arg62Cys & Val214Leu identified in the Korean patients). It also involves wild and mutant type comparison, protein interaction studies, docking and phylogenetic history based on representative ortholog species and also sheds insight into the comparative evolutionary rates of coding sequence across various orthologs. This study gives a time and cost-effective analysis of genes ( PSEN1 and PSEN2 ) underlying AD and genetic alterations that drive development and causes of disease.

The aim of the study was to evaluate the potential diagnostic and prognostic value of gene, Poly A-Binding Protein Interacting Protein 2B ( PAIP2B ) in pancreatic cancer. We used the gene expression data and clinical information of pancreatic adenocarcinoma patients from The Cancer Genome Atlas database and Gene Expression Omnibus database to analyze the expression of PAIP2B in pancreatic cancer samples, and validated the expression of PAIP2B in tumor tissue, using bioinformatics technology to explore the prognostic value of PAIP2B and its possible biological function. A significantly lower level of PAIP2B was observed in pancreatic cancer patients than in controls, and validated by immunohistochemistry. PAIP2B reduced the proliferation and invasion of cancer cells and had a significantly high expression in early stage. Patients with lower levels of PAIP2B had a significantly shorter median survival time than those with higher levels. DNA demethylation played an important role in PAIP2B expression. In addition, PAIP2B expression was significantly associated with the tumor-infiltrating immune cells, especially T cells CD8, T cells CD4 memory resting, macrophages M0, and dendritic cells resting. Our study also found that PAIP2B regulated miRNA function leading to disease progression in pancreatic cancer patients. Our study explored the potential value of PAIP2B as a biological link between prognosis and pancreatic cancer, and provided reference for the follow-up study on the role of PAIP2B in pancreatic cancer.

Background  Microtia is an uncommon congenital malformation ranging from mild anatomic structural abnormalities to partial or complete absence of the ear leading to hearing impairment. Congenital microtia may present as a single malformation (isolated microtia) or sometimes associated with other congenital anomalies involving various organs. Microtia has been classified in three degrees according to the complexity of the auricular malformation and to anotia referred to the total absence of the ear. Genetic role in causing auricular malformation has been widely demonstrated, and genotype-phenotype correlation has been reported in cases of syndromic microtia. Case Presentation  We report here a young patient with a third degree of scale classification and aural atresia. The patient showed unspecific facial dysmorphism, speech delay, precocious teething, hair white patch, and stereotypic anomalous movements. Genetic analysis displayed a de novo 16p13.11 deletion. Conclusion  Microtia with aural atresia is an uncommon and severe birth defect, which affects functional and esthetic aspects, often associated with other malformations. As traumatic this disorder may be for the parents, the microtia and aural atresia are treatable, thanks to the improving and evolving surgical techniques. Based on the genetic analysis and the clinical features observed in the present case, a genotype-phenotype correlation has been proposed.

Background  Noise and drug-induced hearing loss (HL) is becoming more and more serious, but the integration and analysis based on transcriptomics and proteomics are lacking. On the one hand, this study aims to integrate existing public transcriptomic data on noise and gentamicin-induced HL. On the other hand, the study aims to establish the gentamicin and noise-induced HL model of guinea pigs, then to perform the transcriptomic and proteomic analyses. Through comprehensive analysis of the above data, we aim to screen, predict, and preliminarily verify biomarkers closely related to HL. Material and Methods  We screened the Gene Expression Omnibus database to obtain transcriptome data expression profiles of HL caused by noise and gentamicin, then constructed the guinea pig HL model and perform the transcriptomic and proteomic analyses. Differential expression and enrichment analysis were performed on public and self-sequenced data, and common differentially expressed genes (DEGs) and signaling pathways were obtained. Finally, we used proteomic data to screen for common differential proteins and validate common differential expression genes for HL. Results  By integrating the public data set with self-constructed model data set, we eventually obtained two core biomarkers of HL, which were RSAD2 and matrix metalloproteinase-3 (MMP3). Their main function is to regulate the development of sense organ in the inner ear and they are mainly involved in mitogen-activated protein kinase and phosphoinositol-3 kinase/protein kinase B signaling pathways. Finally, by integrating the proteomic data of the self-constructed model, we also found differential expression of MMP3 protein. This also preliminarily and partially verified the above-mentioned core biomarkers. Conclusion and Significance  In this study, public database and transcriptomic data of self-constructed model were integrated, and we screened out two core genes and various signal pathways of HL through differential analysis, enrichment analysis, and other analysis methods. Then, we preliminarily validated the MMP3 by proteomic analysis of self-constructed model. This study pointed out the direction for further laboratory verification of key biomarkers of HL, which is of great significance for revealing the core pathogenic mechanism of HL.

Objectives  Spleen is involved in multiple diseases, the role of the spleen and spleen-derived factors in hepatocellular carcinoma (HCC) is still not clarified. Methods  In the current study, a murine H22 orthotopic hepatoma model was established. Three groups were divided: normal mice, tumor-bearing mice with spleen-preserving, and tumor-bearing mice with splenectomy. Spleen and tumor weights were recorded by weeks 1 and 2. The proportion of myeloid-derived suppressor cell (MDSC) in peripheral blood and tumor tissue was detected using flow cytometry. Protein chip assay was used to compare the differential cytokines between normal liver supernatant and tumor supernatant. The common upregulated cytokines both in spleen and tumor were focused and analyzed using gene expression profiling interactive analysis (GEPIA) database. Enzyme-linked immunosorbent assay was performed to verify the chip result, and to examine CCL9 expression before and after splenectomy. Spleen MDSC was sorted using flow cytometry, and chemotaxis assay was performed to demonstrate whether CCL9 attracted spleen MDSC. Results  The spleen enlarged during tumor progression, and compared with splenectomy group, there were faster tumor growth, shorter survival time, and higher proportions of MDSC in spleen-preserving group. Protein chip assay and GEPIA database revealed CCL9 was the most promising chemokine involved in HCC upregulated both in spleen and tumor tissue. CCL9 attracted MDSC in vitro, the level of CCL9 in tumor tissue was downregulated, and the percentage of MDSC was decreased after splenectomy. Conclusion  The results demonstrate that CCL9 may be derived from spleen; it facilitated HCC growth via the chemotaxis of MDSC, targeting CCL9 may be a promising strategy in HCC treatment.