BMC Medical Genomics最新文献

Osteopetrosis, a group of highly heterogeneous genetic bone disorders, is characterized by deafness, increased bone density, hepatosplenomegaly, pancytopenia and intellectual disability. Osteopetrosis can be divided into three subtypes: autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IARO), and autosomal dominant osteopetrosis (ADO). CLCN7 has been reported to be the most common gene responsible for the ADO-II subtype. In this study, a novel variant, c.175dupA (p.Met59Asnfs*8), of CLCN7 was identified in a Chinese Han consanguineous family with suspected ADO-II. The proband was homozygous for the p.Met59Asnfs*8 variant and exhibited multiple severe phenotypes, including deafness, short stature, brittle bones, optic atrophy, hepatosplenomegaly, intellectual disability, cleft palate and recurrent infection. However, except for the mother of the proband, who presented a series of clinical phenotypes caused by bone marrow failure, all the other family members who were heterozygous had no obvious abnormal phenotypes. Our study suggested that the novel variant p.Met59Asnfs*8 in CLCN7 was very likely pathogenic factor in our suspected ADO-II family. The phenotypes of heterozygous carriers may be affected by incomplete penetrance. Loss of function of CLCN7 caused by nonsense-mediated mRNA decay (NMD) due to the frameshift variant was likely the underlying pathogenic mechanism. This study broadened the mutation spectrum of CLCN7, provided a foundation for timely and effective clinical intervention for related diseases, and demonstrates the importance of genetic counselling.

Fetal pleural effusions can arise in various contexts with different prognosis. They have been reported in fetuses presenting with hereditary or acquired conditions. One particularly rare genetic disorder, known as Knobloch syndrome, seems to emerge as a potential new cause of fetal pleural effusions, associated with severe outcomes. Knobloch syndrome 1 can be caused by biallelic variants in COL18A1. It is primarily characterized by its ophthalmic features, including severe vitreoretinal degeneration with retinal detachment and macular abnormalities. Neurological defects such as encephalocele and developmental delay, along with skeletal and renal malformations, are also associated with the syndrome. The Knobloch syndrome 2 is caused by monoallelic variants in the kinase domain of PAK2. It is less described and seems to also be associated with cardiac and respiratory damage in addition to the Knobloch syndrome 1 phenotype. PAK2 is a ubiquitous protein with a major implication in regulation and remodeling of the cytoskeleton and numerous other cellular pathways. Knobloch-associated variants seem to cause a loss of the kinase function of the protein. Even if the ophthalmic defects are almost constant, PAK2-associated Knobloch syndrome has slightly different features from Knobloch syndrome 1 in which pulmonary and lymphatic damages are still unseen. In a prenatal trio exome sequencing, we identified a novel de novo PAK2 missense variant, NM_002577.4:c.836 A > C, p.(Gln279Pro), classified as likely pathogenic in a 24 weeks of gestation fetus whose only sign was severe bilateral pleural effusion. From a literature review of patients, we recognize this sign as an important antenatal indicator of Knobloch syndrome 2, as it was the first sign identifiable in 2 out of 5 patients. This adds new evidence for the implication of this gene in fetal pleural effusions, with potentially severe outcomes.

Background: To investigate whether the noninvasive preimplantation genetic testing (niPGT) complement conventional preimplantation genetic testing (PGT) in the embryos for aneuploidy.

Results: 40 spent culture medium (SCM) samples from routine embryo culture were collected, and half of each SCM (10 µL) sample was used for whole genome amplification, while the other half was stored at -80 °C for 3-6 months. Thirty-six out of 40 fresh SCM samples were successfully amplified and sequenced. Thirty-six paired frozen-thawed SCM samples showed 100% concordance with the freshly amplified SCM samples. Then, SCM and trophectoderm (TE) samples from 149 blastocysts from 51 couples were collected. A 98.0% successful SCM sample amplification rate (146/149) was achieved. For the 146 paired TE biopsy and SCM samples, the overall concordance rate was 82.9% (121/146). Ten embryos with aneuploid TE results but euploid niPGT results were donated. A 70.0% (7/10) true negative rate was achieved by niPGT with respect to the inner cell mass (ICM) results (TE-positive embryos).

Conclusions: These results suggested that SCM stored at -80 °C for 6 months without affecting niPGT results based on NICSInst amplification.

Background: In recent years, several studies have shown that HSPG2 is associated with the prognosis of specific cancers. The aim of this study was to investigate the prognostic value of HSPG2 in pan-cancer and to analyze its possible mechanisms.

Methods: We used The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to explore the expression of HSPG2 in 33 tumors and corresponding controls. Univariate Cox regression and Kaplan-Meier survival analysis were applied to detect the effects of HSPG2 on overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in patients with these tumors, and to analyze the relationship between HSPG2 and clinical characteristics. And we further analyzed the relationship between HSPG2 and immune infiltration, DNA methylation and single cell function. And GO and KEGG enrichment analyses were performed using HSPG2 co-expressed genes. Finally, we explored the diagnostic efficacy of HSPG2 for diseases of interest and validated it using qPCR experiment.

Results: HSPG2 was lowly expressed in 17 cancers and highly expressed in 11 cancers, and was correlated with patient's clinical characteristics in many cancers. Multivariate regression analysis showed that HSPG2 was an independent prognostic factor for DSS, OS, and PFI in bladder urothelial carcinoma (BLCA) and Mesothelioma (MESO). HSPG2 was correlated with DNA methylation, single-cell function, and immune infiltration in a variety of cancers. HSPG2 exhibited a good diagnostic efficacy for BLCA and MESO. qPCR and western blot results showed that HSPG2 expression was increased in mesothelioma compared to normal controls.

Conclusion: These findings suggest that HSPG2 could be considered as a potential diagnostic and prognostic marker for BLCA and MESO.

Ischemic stroke (IS) represents a harmful neurological disorder with limited treatment options. Ferroptosis accounts for the iron-dependent, nonapoptotic cell death pattern, which shows the feature of fatal lipid ROS accumulation. Nonetheless, ferroptosis-related biomarkers for identifying IS early are currently lacking. The present study focused on investigating the possible ferroptosis-related biomarkers for IS and analyzing their effects on immune infiltration. Altogether five hub differentially expressed ferroptosis-related genes (DEFRGs) were identified from the relevant databases. Additionally, single-cell RNA-sequencing (seq) analysis was conducted for the comprehensive mapping of cell populations based on the IS database. These five hub DEFRGs were analyzed using gene set enrichment analysis, miRNA prediction, and single-cell RNA-seq analysis. A transient middle cerebral artery occlusion mouse model was constructed. We also adopted bioinformatics methods combined with western blot, changes to mitochondria, hematoxylin & eosin staining, Nissl staining, ROS fluorescence staining, immunohistochemistry, and quantitative real-time polymerase chain reaction (qRT-PCR) to show the involvement of ferroptosis in IS progression. The results revealed that nuclear factor erythroid-derived 2-like 2 (Nfe2l2) was the potential candidate biomarker for IS diagnosis, and ferroptosis may be suppressed via the Nfe2l2/HO-1 pathway. Thus, drug targeting Nfe2l2 can shed novel lights on IS treatment.

Background: This study aims to investigate the differences in postoperative prognosis associated with the single nucleotide polymorphism (SNP) rs2228226 (G > C) in gastric adenocarcinoma (GAC) patients.

Methods: This study enrolled 661 patients with locally advanced (pT4a) GAC after surgery. DNA was extracted from their tissues and genotyped for rs2228226 using a MassARRAY Analyzer. Based on the patients' clinical and pathological information, a multifactorial Cox regression analysis was performed to assess the correlation between rs2228226 and the clinical prognosis of pT4a GAC patients. Survival differences among patients who received postoperative chemotherapy were also examined according to rs2228226.

Results: After excluding patients with distant metastasis, loss to follow-up, and those not meeting the inclusion criteria, a total of 463 patients with complete data were included. The rs2228226 genotype distribution was as follows: C/C = 57 (12.3%), G/C = 200 (43.2%), and G/G = 206 (44.5%). Patients with the C/C genotype had significantly shorter disease-free survival (DFS = 12 months) and overall survival (OS = 27 months) compared to those with the G/C or G/G genotype (DFS = 19 months, log-rank P = 0.003; OS = 35 months, log-rank P = 0.002). Further analysis of patients receiving chemotherapy identified the C/C genotype, advanced age, lymph node metastasis, degree of differentiation, and failure to achieve R0 resection as independent risk factors for tumor recurrence and metastasis (P < 0.05). The C/C genotype, lymph node metastasis, and tumor recurrence and metastasis were independent risk factors for mortality (P < 0.05).

Conclusions: In pT4a GAC patients undergoing postoperative chemotherapy, the C/C genotype at rs2228226 is an independent risk factor for tumor recurrence, metastasis, and death. The rs2228226 (G > C) polymorphism may serve as a potential biomarker for predicting prognosis after chemotherapy in GAC.

Background: This study aims to investigate the association between candidate host genetic polymorphisms and COVID-19 susceptibility, severity, hospitalization, hypoxia, and their combined effect, measured by the polygenic risk score (PRS).

Methods: Three hundred and seventy-six Lebanese participants, comprising 151 controls and 225 cases, were included. Clinical data were obtained from questionnaires and medical records. DNA isolated from peripheral blood was genotyped for ACE1 rs1799752, ACE2 rs2074192, TMPRSS2 rs75603675 and OAS1 rs107746771 using TaqMan assays, and for TMPRSS2 rs35074065 using Sanger Sequencing. Candidate genetic variants were analyzed in association with COVID-19 susceptibility, severity, hospitalization and hypoxia, using univariate and multivariate models. PRS constructed from the weighted sum of variants was evaluated in association with COVID-19 outcomes.

Results: In this study, there were no statistically significant differences in the frequencies of candidate variant alleles between cases, controls and within disease outcomes subgroups, after adjustment for confounders. PRS was not associated with COVID-19 susceptibility and hospitalization, it however significantly predicted COVID-19 severity (P = 0.01).

Conclusion: This study highlights the importance of genetic testing for key host genes involved in COVID-19 life cycle and eventually measuring the PRS which proves to be an important tool for prognosis assessment in vulnerable individuals, potentially enhancing patient care.

Background: Non-invasive prenatal testing is widely used for screening common fetal aneuploidy disorders such as trisomy 21, trisomy 18, and trisomy 13. However, its ability to detect rare autosomal trisomies has introduced a new layer of complexity and clinical uncertainty.

Methods: A retrospective analysis was conducted on the prenatal diagnostic results and pregnancy outcomes of cases identified as high-risk for rare autosomal trisomies through non-invasive prenatal testing at the reproductive medicine center, Renmin hospital, Hubei university of medicine, from 2015 to 2023.

Results: 66 cases identified as high-risk for rare autosomeal trisomies, yielding a detection rate of 0.20% (66/33,079). 7 declined amniocentesis, while the others underwent the procedure. Prenatal diagnostic procedures did not confirm the presence of the corresponding rare autosomal trisomy in any of these cases. Among the 66 cases of rare autosomal trisomies (RATs), 5 cases were lost to follow-up, and 1 case underwent termination of pregnancy (TOP) for personal reasons, leaving 60 cases with valid pregnancy outcomes. Of these 60 valid outcomes, 50 (83.33%) resulted in full-term births, while 10 (16.67%) experienced adverse pregnancy outcomes.

Conclusion: Prenatal diagnosis for high-risk rare autosomal trisomies typically reveals a normal karyotype with no detectable chromosomal abnormalities, and most cases can achieve full-term pregnancy outcomes. However, adverse pregnancy outcomes such as preterm birth, fetal demise, placental abnormalities, and intrauterine growth restriction are common and should be given clinical attention and consideration.

Background: The association between educational attainment (EA) and arterial thrombotic disease has been reported, but the causal relationship between EA and venous thromboembolism (VTE) is not clear. We aimed to assess the causal effect of EA on VTE using the two-sample mendelian randomization (MR) method.

Methods: Data mining was conducted on the genome wide association studies (GWAS), with exposure factor EA and outcome factor VTE. Two-sample Mendelian Randomization (TSMR) analysis was conducted, with the results obtained from the random effects inverse variance weighted method (IVW). Use the MR-Egger method for pleiotropy analysis and leave one method for sensitivity analysis to verify the reliability of the data.

Results: Genetically predicted decreased EA was associated with a decreased risk of VTE in both the FinnGen consortium and UK Biobank (FinnGen-VTE: OR = 0.848; 95% CI 0.776-0.927; P = 2.84 × 10^-4; UKB-VTE OR = 0.996; 95% CI 0.994-0.999; P = 0.008) under a multiplicative random-effects IVW model. Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected.

Conclusions: The MR technique instructed a potential inverse causative relationship between EA and occurrence of VTE. Therefore, patients with low EA should be more vigilant about the occurrence of VTE.

Background: Screening tests, particularly liquid biopsy with circulating miRNAs, hold significant potential for non-invasive cancer detection before symptoms manifest.

Methods: This study aimed to identify biomarkers with high sensitivity and specificity for multiple and specific cancer screening. 972 Serum miRNA profiles were compared across thirteen cancer types and healthy individuals using weighted miRNA co-expression network analysis. To prioritize miRNAs, module membership measure and miRNA trait significance were employed. Subsequently, for specific cancer screening, gastric cancer was focused on, using a similar strategy and a further step of preservation analysis. Machine learning techniques were then applied to evaluate two distinct miRNA panels: one for multi-cancer screening and another for gastric cancer classification.

Results: The first panel (hsa-miR-8073, hsa-miR-614, hsa-miR-548ah-5p, hsa-miR-1258) achieved 96.1% accuracy, 96% specificity, and 98.6% sensitivity in multi-cancer screening. The second panel (hsa-miR-1228-5p, hsa-miR-1343-3p, hsa-miR-6765-5p, hsa-miR-6787-5p) showed promise in detecting gastric cancer with 87% accuracy, 90% specificity, and 89% sensitivity.

Conclusions: Both panels exhibit potential for patient classification in diagnostic and prognostic applications, highlighting the significance of liquid biopsy in advancing cancer screening methodologies.