Abstract
Background
Polycystic ovary syndrome (PCOS) is a complex reproductive disorder, that affects approximately 5–10% of women of reproductive age. The disease is complex because its evolution ...may be impacted by genetic, lifestyle and environmental factors. Previous studies have emphasized the important roles of estrogen receptors in the pathogenesis of PCOS.
Objective
To use whole exome sequencing (WES) to assess possible pathogenic factors in a PCOS patient who exhibited estrogen insensitivity during hormone replacement therapy (HRT) treatment.
Methods
Genome sequencing and variant filtering via WES were performed in a patient with PCOS. DNA extraction from 364 unrelated female controls without PCOS was followed by PCR amplification, Sanger sequencing and sequence alignment. Evolutionary conservation analysis, protein structural modelling and in silico prediction were applied to analyse the potential pathogenicity of the novel
ESR1
mutation.
Result(s)
During the controlled ovarian hyperstimulation (COH) period of an IVF cycle, the patient experienced markedly prolonged ovarian stimulation due to a poor response to gonadotropins (Gn) and elevated serum FSH. A novel heterozygous
ESR1
mutation, c.619G > A/p.A207T, leading to the replacement of a highly conserved alanine with a threonine, was identified in this patient, via WES analysis. This novel variant was not identified in 364 unrelated female controls without PCOS, or in the Exome Aggregation Consortium (ExAC) or 1000 Genome Project.
Conclusion(s)
We identified a novel heterozygous
ESR1
mutation in a Han Chinese PCOS woman exhibiting clinical signs of estrogen insensitivity. This study may provide new strategies for IVF therapy, especially for patients who exhibit estrogen insensitivity during IVF cycle.
The retina and its adjacent supporting tissues – retinal pigmented epithelium (RPE) and choroid – are critical structures in human eyes required for normal visual perception. Abnormal changes in ...these layers have been implicated in diseases such as age-related macular degeneration and glaucoma. With the advent of high-throughput methods, such as serial analysis of gene expression, cDNA microarray, and RNA sequencing, there is unprecedented opportunity to facilitate our understanding of the normal retina, RPE, and choroid. This information can be used to identify dysfunction in age-related macular degeneration and glaucoma. In this review, we describe the current status in our understanding of these transcriptomes through the use of high-throughput techniques.
•We provide a brief overview of the eye structure with an emphasis on its posterior layers•We summarize the data and techniques used to characterize the human retina and RPE/choroid transcriptome
Unsubstantiated concerns have been raised on the potential correlation between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infertility, leading to vaccine hesitancy ...in reproductive-aged population. Herein, we aim to evaluate the impact of inactivated SARS-CoV-2 vaccination on embryo ploidy, which is a critical indicator for embryo quality and pregnancy chance. This was a retrospective cohort study of 133 patients who underwent preimplantation genetic testing for aneuploidy (PGT-A) cycles with next-generation sequencing technology from June 1st 2021 to March 17th 2022 at a tertiary-care medical center in China. Women fully vaccinated with two doses of Sinopharm or Sinovac inactivated vaccines (n = 66) were compared with unvaccinated women (n = 67). The primary outcome was the euploidy rate per cycle. Multivariate linear and logistic regression analyses were performed to adjust for potential confounders. The euploidy rate was similar between vaccinated and unvaccinated groups (23.2 + or - 24.6% vs. 22.6 + or - 25.9%, P = 0.768), with an adjusted beta of 0.01 (95% confidence interval CI: -0.08-0.10). After frozen-thawed single euploid blastocyst transfer, the two groups were also comparable in clinical pregnancy rate (75.0% vs. 60.0%, P = 0.289), with an adjusted odds ratio of 6.21 (95% CI: 0.76-50.88). No significant associations were observed between vaccination and cycle characteristics or other laboratory and pregnancy outcomes. Inactivated SARS-CoV-2 vaccination had no detrimental impact on embryo ploidy during in vitro fertilization treatment. Our finding provides further reassurance for vaccinated women who are planning to conceive. Future prospective cohort studies with larger datasets and longer follow-up are needed to confirm the conclusion.
Purpose
To explore the impact of inactivated COVID-19 vaccination on ovarian reserve as assessed by serum anti-Müllerian hormone (AMH) concentration.
Methods
A total of 3160 women were included in ...this single-center retrospective cohort study between June 2021 and October 2022. Vaccination information were collected from official immunization records available in personal mobile apps. Serum AMH was qualified by electrochemiluminescence immunoassay and compared with previous measurement data within three years. Women were categorized to the vaccinated group if they received two doses of inactivated COVID-19 vaccines (Sinopharm or Sinovac) between AMH tests (
n
= 488), and to the control group if not vaccinated (
n
= 2672). Propensity score matching and multivariate linear regression were performed to control for potential confounders. The main outcome measures were the numeric AMH change and percentage AMH change between the two tests.
Results
There were 474 women left in each group after matching all baseline characteristics. The mean interval from the first to second AMH measurement was 508.0 ± 250.2 and 507.5 ± 253.6 days for vaccinated and unvaccinated women, respectively (
P
= 0.680). Both groups had a significant AMH decrease in the second test compared with the first test (
P
= 0.001). However, the second AMH level remained comparable between groups (3.26 ± 2.80
vs.
3.24 ± 2.61 ng/mL,
P
= 0.757). Similarly, no significant differences were observed in numerical (-0.14 ± 1.32
vs.
-0.20 ± 1.56 ng/mL,
P
= 0.945) and percentage (2.33 ± 58.65
vs.
0.35 ± 48.42%,
P
= 0.777) AMH changes. The results were consistent in sub-analyses for women aged <35 and ≥35 years. There were also no significant differences when vaccinated women were divided according to the time interval after vaccination: ≤30, 31–60, 61–90, and ≥91 days.
Conclusion
Our study provides the first evidence that inactivated COVID-19 vaccination has no measurable detrimental effect on ovarian reserve, regardless of female age and vaccination interval. This reassuring finding adds to the safety evidence of COVID-19 vaccine in fertility, and should be useful to promote vaccine acceptance. Multicenter prospective cohort studies are needed to validate our conclusion.
To evaluate the association of endometrial thickness (EMT) with obstetric and neonatal outcomes in women with polycystic ovary syndrome (PCOS).
A total of 1755 subfertile PCOS women with singleton ...livebirths after frozen-thawed embryo transfer were included between January 2009 and September 2019. Main obstetric outcomes were hypertensive disorders in pregnancy and abnormal placentation. Main neonatal outcomes were preterm birth (PTB), low birthweight (LBW) and small-for-gestational age (SGA). Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by univariate and multivariate logistic regression analyses.
Each millimeter decrease in EMT was related to a 9% (adjusted OR 1.09, 95% CI 1.00-1.19;
= 0.053), 14% (adjusted OR 1.14, 95% CI 1.02-1.28;
= 0.002) and 22% (adjusted OR 1.22, 95% CI 1.07-1.38;
= 0.003) higher risk of PTB, LBW and SGA, respectively. Compared to women with EMT >13 mm, women with EMT ≤8 mm also had significantly higher risk of PTB (adjusted OR 3.79, 95% CI 1.53-9.39;
= 0.004), LBW (adjusted OR 4.33, 95% CI 1.39-13.50;
= 0.012) and SGA (adjusted OR 6.38, 95% CI 1.78-22.83;
= 0.004). These associations remained consistent in further subgroup analysis by endometrial preparation regimen and in sensitivity analyses among nulligravida women or women without adverse obstetric outcomes. No significant differences were found in the incidence of several pregnancy complications across EMT categories.
Decreased EMT was independently associated with increased risk of PTB, LBW and SGA in women with PCOS.
Background Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), ...which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint. Objective We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders. Methods A family with multiple members with a diagnosis of CVID was screened by using whole-exome sequencing. The proband and other subjects with mutations associated with CVID-like phenotypes were screened through the SVM algorithm from our recent CVID genome-wide association study. RT-PCR, protein immunoblots, and in vitro plasmablast differentiation assays were performed on patient and control EBV lymphoblastoids cell lines. Results Exome sequencing identified a novel heterozygous mutation in IRF2BP2 (c.1652G>A:p.S551N) in affected family members. Transduction of the mutant gene into control human B cells decreased production of plasmablasts in vitro , and IRF2BP2 transcripts and protein expression were increased in proband versus control EBV-immortalized lymphoblastoid cell lines. The SVM algorithm categorized the proband and subjects with other immunodeficiency-associated gene variants in TACI , BAFFR , ICOS , CD21 , LRBA , and CD27 as genetically dissimilar from polygenic CVID. Conclusion A novel IRFBP2 mutation was identified in a family with autosomal dominant CVID. Transduction experiments suggest that the mutant protein has an effect on B-cell differentiation and is likely a monogenic cause of the family's CVID phenotype. Successful grouping by the SVM algorithm suggests that our family and other subjects with rare immunodeficiency disorders cluster separately and lack the genetic pattern present in polygenic CVID cases.
Asthma is a complex condition largely attributed to the interactions among genes and environments as a heterogeneous phenotype. Obesity is significantly associated with asthma development, and ...genetic studies on obese vs. non-obese asthma are warranted.
To investigate asthma in the minority African American (AA) population with or without obesity, we performed a whole genome sequencing (WGS) study on blood-derived DNA of 4289 AA individuals, included 2226 asthma patients (1364 with obesity and 862 without obesity) and 2006 controls without asthma. The burden analysis of functional rare coding variants was performed by comparing asthma vs. controls and by stratified analysis of obese vs. non-obese asthma, respectively.
Among the top 66 genes with P < 0.01 in the asthma vs. control analysis, stratified analysis by obesity showed inverse correlation of natural logarithm (LN) of P value between obese and non-obese asthma (r = - 0.757, P = 1.90E-13). Five genes previously reported in a genome-wide association study (GWAS) on asthma, including TSLP, SLC9A4, PSMB8, IGSF5, and IKZF4 were demonstrated association in the asthma vs. control analysis. The associations of IKZF4 and IGSF5 are only associated with obese asthma; and the association of SLC9A4 is only observed in non-obese asthma. In addition, the association of RSPH3 (the gene is related to primary ciliary dyskinesia) is observed in non-obese asthma.
These findings highlight genetic heterogeneity between obese and non-obese asthma in patients of AA ancestry.
Mutations in the sarcomeric protein filamin C (FLNC) gene have been linked to hypertrophic cardiomyopathy (HCM), as they have been determined to increase the risk of ventricular arrhythmia and sudden ...death. Thus, in this study, we identified a novel missense mutation of FLNC in a Chinese family with HCM, and, interestingly, a second novel truncating mutation of MYLK2 was discobered in one family member with different phenotype.We performed whole-exome sequencing in a Chinese family with HCM of unknown cause. To determine and confirm the function of a novel mutation of FLNC, we introduced the mutant and wild-type gene into AC16 cells (human cardiomyocytes): we then used western blotting to analyze the expression of FLNC in subcellular fractions, and confocal microscope to observe the subcellular distribution of the protein.As per our findings, we were able to identify a novel missense single nucleotide variant (FLNC c.G5935A p.A1979T) in the family, which segregates with the disease. FLNC expression levels were observed to be equivalent in both wild-type and p.A1979T cardiomyocytes. However, the expression of the mutant protein has resulted in cytoplasmic protein aggregations, in contrast to wild-type FLNC, which was distributed in the cytoplasm and did not form aggregates. Unexpectedly, a second truncating mutation, NM_033118:exon8:c.G1138T:p.E380X of the MYLK2 gene, was identified in the mother of the proband with dilated cardiomyopathy, which was not found in other subjects.We then identified the FLNC A1979T mutation as a novel pathogenic variant associated with HCM in a Chinese family as well as a second causal mutation in a family member with a distinct phenotype. The possibility that there is more than one causal mutation in cardiomyopathy warrants clinical attention, especially for patients with atypical clinical features.
There is a current pandemic of a new type of coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The number of confirmed infected cases has been rapidly increasing. This ...paper analyzes the characteristics of SARS-CoV-2 in comparison with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and influenza. COVID-19 is similar to the diseases caused by SARS-CoV and MERS-CoV virologically and etiologically, but closer to influenza in epidemiology and virulence. The comparison provides a new perspective for the future of the disease control, and offers some ideas in the prevention and control management strategy. The large number of infectious people from the origin, and the highly infectious and occult nature have been two major problems, making the virus difficult to eradicate. We thus need to contemplate the possibility of long-term co-existence with COVID-19.
RNA-seq has been a powerful method to detect the differentially expressed genes/long non-coding RNAs (lncRNAs) in schizophrenia (SCZ) patients; however, due to overfitting problems differentially ...expressed targets (DETs) cannot be used properly as biomarkers. This study used machine learning to reduce gene/non-coding RNA features. Dorsolateral prefrontal cortex (dlpfc) RNA-seq data from 254 individuals was obtained from the CommonMind consortium. The average predictive accuracy for SCZ patients was 67% based on coding genes, and 96% based on long non-coding RNAs (lncRNAs). Machine learning is a powerful algorithm to reduce functional biomarkers in SCZ patients. The lncRNAs capture the characteristics of SCZ tissue more accurately than mRNA as the former regulate every level of gene expression, not limited to mRNA levels.
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