BMC Medical Genomics最新文献

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an exceptionally contagious single-stranded RNA virus with a strong positive contagion. The COVID-19 pandemic refers to the swift worldwide dissemination of SARS-CoV-2 infection, which began in late 2019. The COVID-19 epidemic has disrupted many cancer treatments. A few reports indicate that the prevalence of SARS-CoV-2 has disrupted the treatment of breast cancer patients (BCs). However, the role of SARS-CoV-2 in the occurrence and prognosis of BC has not been elucidated. Here, we applied bioinformatics to construct a prognostic signature of SARS-CoV-2-related genes (SCRGs). Specifically, weighted gene co-expression network analysis (WGCNA) was utilized to extract co-expressed genes of differentially expressed genes (DEGs) in breast cancer and SCRGs. Then, we utilized the least absolute shrinkage and selection operator (LASSO) algorithm and univariate regression analysis to screen out three hub genes (DCTPP1, CLIP4 and ANO6) and constructed a risk score model. We further analyzed tumor immune invasion, HLA-related genes, immune checkpoint inhibitors (ICIs), and sensitivity to anticancer drugs in different SARS-CoV-2 related risk subgroups. In addition, we have developed a nomination map to expand clinical applicability. The results of our study indicate that BCs with a high-risk score are linked to negative outcomes, lower immune scores, and reduced responsiveness to anticancer medications. This suggests that the SARS-CoV-2 related signature could be used to guide prognosis assessment and treatment decisions for BCs.

Background: Synpolydactyly (SPD) is mainly caused by mutations of polyalanine expansion (PAE) in the transcription factor gene HOXD13 and the involved cell types and signal pathway are still not clear possible pathways and single-cell expression characteristics of limb bud in HOXD13 PAE mice was analyzed in this study.

Method: We investigated a previous study of a mouse model with SPD and conducted weighted gene co-expression network analysis (WGCNA) using a single-cell RNA sequencing dataset from limb bud cells of SPD mouse model of HOXD13 + 7A heterozygote.

Results: Analysis of WGCNA revealed that synpolydactyly-associated Hoxd13 PAEs alter the immune response and osteoclast differentiation, and enhance DNA replication. Bmp4, Hand2, Hoxd12, Lnp, Prrx1, Gmnn, and Cdc6 were found to play potentially key roles in synpolydactyly.

Conclusions: These findings evaluated the main genes related to SPD with PAE mutations in HOXD13 and advance our understanding of human limb development.

Background: Although previous observational studies have shown an association between venous thromboembolism (VTE) and atrial fibrillation (AF), the underlying causal relationship between them remains uncertain.

Methods and results: This two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal relationship between VTE and AF. The VTE dataset were obtained from FinnGen, including 9,176 cases and 209,616 controls. Meanwhile a genome-wide association study (GWAS) of 60,620 individuals with AF and 970,216 control subjects identified genetic variations associated with AF. The principal MR analytic approach used in this study is the inverse-variance weighting (IVW) method. Furthermore, we performed complementary MR analyses, including the MR-Egger, Weighted median (WM), and Weighted Mode. MR pleiotropy residual sum was applied to identify pleiotropy. The MR analysis showed suggestive causal associations between VTE and the risk of AF (p = 0.0245, OR [95%CI]: 1.027 [1.003, 1.051]). The reverse MR analysis found that genetic susceptibility to AF was not significantly associated with VTE, as determined by the IVW method (p = 0.7773). The robustness of these findings was corroborated through MR sensitivity analyses.

Conclusions: There is a unidirectional causal relationship between VTE and AF, meaning that VTE is a causal risk factor for AF, whereas no effect of AF on VTE was identified.

Postoperative abdominal adhesion is one of the most common complications after abdominal surgery. The Toll-like receptor 4 (TLR4) signaling pathway is one of the most common inflammation-related pathways, and it has been demonstrated that TLR4 is highly expressed in adhesive tissues; however, the function of TLR4 in adhesion formation has not yet been studied. In the present study, the expression of TLR4 was first detected by immunohistochemical (IHC) and double-immunofluorescence staining in 40 mice, which were randomly divided into four groups, and sacrificed at 1, 3, 5 and 7 days after surgery. Subsequently, another 40 mice were randomly divided into five groups; with the exception of the sham group, the other groups were modeled and treated with saline that contained DMSO, sodium hyaluronate (HA), TAK-242 or TAK-242 + HA (applied to damaged peritoneal wounds). A total of 7 days after surgery, the mice were sacrificed and specimens were collected. Inflammation was detected by hematoxylin and eosin staining, and ELISA of transforming growth factor- β1 (TGF-β1) and interleukin-6 (IL-6); collagen deposition was examined by Masson staining and IHC staining of α-SMA; and reactive oxygen species (ROS) were detected by ROS staining and malondialdehyde (MDA) assay. The results revealed that TLR4 was highly expressed in the adhesive tissues at 3, 5 and 7 days after surgery. In addition, TAK-242 + HA treatment could reduce abdominal adhesion formation, exhibiting lower Nair's score and inflammation scores, lower TGF-β1 and IL-6 levels, and lower collagen thickness and α-SMA levels compared with those in the control group. In addition, the TAK-242 + HA group had lower levels of ROS and MDA compared with those in the control group. The present study revealed that TLR4 was highly expressed in the process of adhesion formation and its inhibitor, TAK-242, combined with HA, could reduce adhesion formation by reducing inflammation and ROS, and alleviating collagen deposition.

Background: New diagnostic tools are needed to improve the diagnosis and risk stratification of cutaneous melanoma. Disease-specific microRNA signatures have been previously described via NanoString profiling of solid biopsy tissue and plasma. This study validated these signatures via next-generation sequencing technology and compared their performance against clinical metrics and other published melanoma signatures.

Methods: RNA from 64 plasma and 60 FFPE biopsy samples from individuals with invasive melanoma or related benign/control phenotypes was extracted and enriched for microRNA. RNA sequencing was performed to compute MEL38/MEL12 signature scores. The results were evaluated with published NanoString and RNA sequencing datasets, comprising 548 solid tissue samples and 217 plasma samples, to predict disease status and patient outcome.

Results: The MEL38 diagnostic signature classifies patients into discrete diagnostic groups via RNA sequencing in either solid tissue or plasma (P < 0.001). In solid tissue, the prognostic MEL12 signature stratifies patients into low-, intermediate- and high-risk groups, independent of clinical covariates. The hazard ratios for 10-year overall survival, based on observed survival intervals, were 2.2 (MEL12 high-risk vs low-risk, P < 0.001) and 1.8 (intermediate-risk vs low-risk, P < 0.001), outperforming other published prognostic models. MEL12 also exhibited prognostic significance in the plasma of 42 patients with invasive disease.

Conclusions: The MEL38 and MEL12 signatures can be assessed in either solid tissue or plasma using RNA-seq and are strong predictors of disease state and patient outcome. Compared with other genomic methods, MEL12 was shown to be the strongest predictor of poor prognosis. MicroRNA expression profiling offers objective, accurate genomic information about a patient's likelihood of invasive melanoma and prognosis.

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Over 700 syndromes associated with hearing loss (HL) have been identified. Labyrinthine aplasia, microtia, and microdontia (LAMM syndrome, OMIM: 610706) is a rare HL syndrome characterized by congenital sensorineural HL, labyrinthine aplasia, type I microtia and microdontia, which is caused by biallelic variants in the FGF3 gene. Using Whole-exome sequencing (WES), we identified a novel missense FGF3 variant (c.137G > C, p. Arg46Pro (NM_005247.4) in three unrelated Uyghur ethnic families. This variant is classified as a variant of uncertain significance according to ACMG guidelines, with the applied criteria of PM3, PM2_Supporting, PP3 and PP4. Patients from the three families revealed variable clinical features. We found a novel phenotype, sparse hair, in one of the proband. Our findings expanded the variant and phenotype spectrum of LAMM syndrome and provided new insights to the diagnose and pathogenesis investigation of the disease.

Background: X-linked recessive chondrodysplasia punctata 1 (CDPX1) is a rare congenital skeletal dysplasia characterized by stippled epiphyses, nasal hypoplasia, and brachytelephalangy. ARSL (formerly known as ARSE), a member of the sulfatase gene family located on Xp22.3, has been identified as the causative gene for CDPX1. The high clinical and genetic heterogeneity of CDPX1 presents a challenge to prenatal diagnosis.

Case presentation: A G1P0 woman in her 30s with an unremarkable prenatal course presented in the second trimester. Maternal diseases, tobacco, alcohol, and drug history during pregnancy were denied. Obstetrical ultrasound examination revealed a flattened nose and a flattened midface with echogenic alterations of lumbar spinous process in the fetus. Amniocentesis was performed for genetic testing. A normal karyotype and a negative result of CNV-seq were obtained. However, Whole exome sequencing (WES) in trios revealed a hemizygous ARSL variant [NM_000047.3:c.1108del p.(Trp370Glyfs*35)] in the fetus, which was maternally inherited as confirmed by Sanger sequencing. This variant was absent from the genomAD and HGMD databases. According to the ACMG guidelines, this variant was interpreted as likely pathogenic (PVS1 + PM2_Supporting). The couple decided to terminate the pregnancy. After induction of labour, a severe nasal hypoplasia was noted; and brachytelephalangy was not remarkable. Postmortem digital X-ray imaging revealed symmetrical stippled epiphyses of the vertebrae in all spine regions and enlargement of spinous process of L1-L4 vertebrae.

Conclusion: A novel frameshift deletion variant of ARSL and the associated fetal phenotype have been identified. This study provides useful information for prenatal diagnosis and genetic counseling of CDPX1.

Background: Androgen insensitivity syndrome (AIS) is a rare genetic disorder characterized by resistance to androgens, mainly due to mutations in the androgen receptor (AR) gene. It can manifest as complete AIS, partial AIS and mild AIS. While there have been studies linking specific AR gene mutations to AIS phenotypes, different clinical AIS phenotypes are also reported in patients with the same AR gene mutation. So far, the precise correlations between phenotypes and genotypes remain incompletely understood.

Methods: We conducted a thorough investigation involving four patients diagnosed with different types of AIS from a single Chinese family. Clinical manifestations, laboratory examinations, and fertility outcomes were well-documented. Furthermore, we performed genetic sequencing to detect possible pathogenetic variants.

Results: Whole exome sequencing identified a hemizygous missense variant (c.2263T > C; p.Phe755Leu) of AR gene in all four affected patients with different degrees of undermasculinisation and heterogeneous spermatogenesis. The proband, diagnosed with partial AIS, opted for treatment with donated sperm due to non-obstructive azoospermia, while their older sibling, diagnosed with complete AIS, was raised as a girl. His two maternal uncles were both diagnosed with mild AIS, the older uncle fathered two girls naturally, whereas the younger uncle utilized assisted reproductive technology to conceive a boy because of severe oligoasthenozoospermia.

Conclusion: Our study first identified the same AR variant (c.2263T > C;p.Phe755Leu) in four affected patients displaying highly diverse phenotypes of AIS and fertility outcomes, thereby significantly expanding the phenotypic spectrum of AIS. Notably, we presented a clear insight into different fertility outcomes of AIS patients with identical AR (c.2263T > C;p.Phe755Leu) variant, which provided reliable evidence that males harboring this variant may obtain biological offspring naturally or in combination with assisted reproductive technology. Furthermore, our study underscored the potential role of androgen concentration in shaping the phenotypic diversity of AIS, warranting further investigation.