Congenital heart defects (CHDs) are a common birth defect, affecting approximately 1% of newborn children in the United States. As previously reported, a significant number of CHDs are potentially ...attributed to altered copy number variants (CNVs). However, as many genomic variants are rare, a large-scale CNV triad study is necessary to characterize the genetic architecture of CHD. We used whole-exome sequencing (WES) data generated by the Pediatric Cardiac Genomics Consortium (PCGC), including a discovery dataset of 2,103 individuals from 760 nuclear family trios and an independent replication set of 4,808 individuals from 1,712 trios. The candidate targets uncovered were further validated through different platforms, including the Omni single-nucleotide polymorphism (SNP) array chip in 1,860 individuals and the whole-genome sequencing (WGS) data in 33 trios. The genes harboring CNVs of interest were then investigated for expression alternations based on cardiac tissue RNA-Seq data. We identified multiple CNVs in the WES data that associated with specific sub-phenotypes of CHD in approximately 2,400 families, including 98
CNV regions. We identified five CNV loci harboring
,
,
,
, and
, respectively, where those genes are highly expressed in human heart and/or mouse embryo heart at 15 days. Five novel CNV loci were uncovered, demonstrating altered expression of the respective candidate genes involved. To our knowledge, this is the largest trio-based WES study of CHD and, in addition to uncovering novel CHD targets, presents an extensive resource with the potential to provide important insights to the architecture and impact of CNVs in CHD.
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we ...sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA. Multiple novel rare recurrent variants were identified in exonic regions, functionally classified as stop-gains and frameshifts for known ADHD genes. Deletion in introns of the protocadherins families and the ncRNA
were identified in two independent EA ADHD patients. A meta-analysis of the two ethnicities for differential ADHD recurrent variants compared to controls shows a small number of overlaps. These results suggest that rare recurrent variants in noncoding regions may be involved in the pathogenesis of ADHD in children of both AA and EA ancestry; thus, WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.
Objectives
To investigate the relationship between prior coronavirus disease 2019 (COVID‐19) infection in females and subsequent treatment outcomes of assisted reproductive technology (ART).
Methods
...A systematic literature review was carried out up to 16 December 2022, in PubMed, Web of Science, EMBASE, and Cochrane Library. Random‐effect models were adopted to estimate the pooled effects as mean differences (MDs) or odds ratios (ORs). I2 statistic and Egger's test were applied to assess heterogeneity and publication bias, respectively.
Results
After screening 1480 records, 15 cohort studies totalling 1905 cycles were included in this meta‐analysis. In a comparison of previously COVID‐19‐infected versus uninfected women, no significant differences were observed in the primary outcomes of the retrieved oocytes number (MD = 0.06; 95% confidence interval CI: ‐0.75–0.88; I2 = 0) and clinical pregnancy rate (OR = 0.96; 95% CI: 0.74–1.24; I2 = 0). Pooled analyses of other predefined outcomes, which encompassed four cycle characteristics, six laboratory indicators and four pregnancy results, also showed no adverse effects of prior COVID‐19 infection. Most outcomes remained consistent after further sensitivity and subgroup analyses, and no significant publication bias was observed.
Conclusions
Our work provides the first systematic evidence that COVID‐19 infection history in females may have no measurable detrimental impact on the subsequent ART cycle. More data are needed to assess the live birth outcome and the optimal time interval from infection to assisted reproduction.
Rubinstein-Taybi syndrome (RTS) is a rare, congenital, plurimalformative, and neurodevelopmental disorder. Previous studies have reported that large deletions contribute to more severe RTS phenotypes ...than those caused by CREBBP point mutations, suggesting a concurrent pathogenetic role of flanking genes, typical of contiguous gene syndromes, but the detailed genetics are unclear.
This study presented a rare case of Rubinstein-Taybi (RT) syndrome with serious cardiac abnormalities. Based on the clinical and genetic analysis of the patient, the ADCY9 gene deletion was highlighted as a plausible explanation of cardiac abnormalities. In adcy9 morphant zebrafish, cardiac malformation was observed. Immunofluorescence study disclosed increased macrophage migration and cardiac apoptosis. RNA sequencing in zebrafish model highlighted the changes of a number of genes, including increased expression of the mmp9 gene which encodes a matrix metalloproteinase with the main function to degrade and remodel extracellular matrix.
In this study, we identified a plausible new candidate gene ADCY9 of CHD through the clinical and genetic analysis of a rare case of Rubinstein-Taybi (RT) syndrome with serious cardiac abnormalities. By functional study of zebrafish, we demonstrated that deletion of adcy9 is the causation for the cardiac abnormalities. Cardiac apoptosis and increased expression of the MMP9 gene are involved in the pathogenesis.
This study aimed to identify the genetics underlying dominant forms of inherited retinal dystrophies using whole exome sequencing (WES) in six families extensively screened for known mutations or ...genes. Thirty-eight individuals were subjected to WES. Causative variants were searched among single nucleotide variants (SNVs) and insertion/deletion variants (indels) and whenever no potential candidate emerged, copy number variant (CNV) analysis was performed. Variants or regions harboring a candidate variant were prioritized and segregation of the variant with the disease was further assessed using Sanger sequencing in case of SNVs and indels, and quantitative PCR (qPCR) for CNVs. SNV and indel analysis led to the identification of a previously reported mutation in PRPH2. Two additional mutations linked to different forms of retinal dystrophies were identified in two families: a known frameshift deletion in RPGR, a gene responsible for X-linked retinitis pigmentosa and p.Ser163Arg in C1QTNF5 associated with Late-Onset Retinal Degeneration. A novel heterozygous deletion spanning the entire region of PRPF31 was also identified in the affected members of a fourth family, which was confirmed with qPCR. This study allowed the identification of the genetic cause of the retinal dystrophy and the establishment of a correct diagnosis in four families, including a large heterozygous deletion in PRPF31, typically considered one of the pitfalls of this method. Since all findings in this study are restricted to known genes, we propose that targeted sequencing using gene-panel is an optimal first approach for the genetic screening and that once known genetic causes are ruled out, WES might be used to uncover new genes involved in inherited retinal dystrophies.
HER2, which is associated with clinically aggressive disease, is overexpressed in 15-20% of breast cancers (BC). The host immune system participates in the therapeutic response of HER2
breast cancer. ...Identifying genetic programs that participate in ErbB2-induced tumors may provide the rational basis for co-extinction therapeutic approaches. Peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Herein, genetic deletion of endogenous
restrained mammary tumor progression, lipogenesis, and induced local mammary tumor macrophage infiltration, without affecting other tissue hematopoietic stem cell pools. Endogenous
induced expression of both an EphA2-Amphiregulin and an inflammatory INFγ and Cxcl5 signaling module, that was recapitulated in human breast cancer.
bound directly to growth promoting and proinflammatory target genes in the context of chromatin. We conclude
promotes ErbB2-induced tumor growth and inflammation and represents a relevant target for therapeutic coextinction. Herein, endogenous
promoted ErbB2-mediated mammary tumor onset and progression. PPARγ1 increased expression of an EGF-EphA2 receptor tyrosine kinase module and a cytokine/chemokine 1 transcriptional module. The induction of a pro-tumorigenic inflammatory state by
may provide the rationale for complementary coextinction programs in ErbB2 tumors.
IntroductionPolycystic ovary syndrome (PCOS) is one of the leading causes of female infertility, affecting around 5% of women of childbearing age in China. Vitamin D insufficiency is common in women ...with PCOS and is associated with lower live birth rates. However, evidence regarding the effectiveness of vitamin D supplementation in women with PCOS is inconclusive. This multicentre randomised, double-blinded, placebo-controlled trial aims to evaluate the effectiveness of vitamin D supplementation prior to in vitro fertilisation (IVF) on the live birth rate in women with PCOS.Methods and analysisWe plan to enrol women with PCOS scheduled for IVF. After informed consent, eligible participants will be randomised in a 1:1 ratio to receive oral capsules of 4000 IU vitamin D per day or placebo for around 12 weeks until the day of triggering. All IVF procedures will be carried out routinely in each centre. The primary outcome is live birth after the first embryo transfer. The primary analysis will be by intention-to-treat analysis. To demonstrate or refute that treatment with vitamin D results in a 10% higher live birth rate than treatment with placebo, we need to recruit 860 women (48% vs 38% difference, anticipating 10% loss to follow-up and non-compliance, significance level 0.05 and power 80%).Ethics and disseminationThis study has been approved by the Ethics Committee in Women’s Hospital of Zhejiang University on 2 March 2020 (reference number: IRB-20200035-R). All participants will provide written informed consent before randomisation. The results of the study will be submitted to scientific conferences and a peer-reviewed journal.Trial registration numberNCT04082650.
Phosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense mutations in PRPS1 that lead to three different phenotypes: Arts Syndrome (MIM 301835), ...X-linked Charcot-Marie-Tooth (CMTX5, MIM 311070) or X-linked non-syndromic sensorineural deafness (DFN2, MIM 304500). All three are X-linked recessively inherited and males affected display variable degree of central and peripheral neuropathy. We applied whole exome sequencing to a three-generation family with optic atrophy followed by retinitis pigmentosa (RP) in all three cases, and ataxia, progressive peripheral neuropathy and hearing loss with variable presentation.
Whole exome sequencing was performed in two affecteds and one unaffected member of the family. Sanger sequencing was used to validate and segregate the 12 candidate mutations in the family and to confirm the absence of the novel variant in PRPS1 in 191 controls. The pathogenic role of the novel mutation in PRPS1 was assessed in silico and confirmed by enzymatic determination of PRS activity, mRNA expression and sequencing, and X-chromosome inactivation.
A novel missense mutation was identified in PRPS1 in the affected females. Age of onset, presentation and severity of the phenotype are highly variable in the family: both the proband and her mother have neurological and ophthalmological symptoms, whereas the phenotype of the affected sister is milder and currently confined to the eye. Moreover, only the proband displayed a complete lack of expression of the wild type allele in leukocytes that seems to correlate with the degree of PRS deficiency and the severity of the phenotype. Interestingly, optic atrophy and RP are the only common manifestations to all three females and the only phenotype correlating with the degree of enzyme deficiency.
These results are in line with recent evidence of the existence of intermediate phenotypes in PRS-I deficiency syndromes and demonstrate that females can exhibit a disease phenotype as severe and complex as their male counterparts.
Due to the influence of shock wave and turbulence, supersonic density field exhibits strongly inhomogeneous and unsteady characteristics. Applying traditional density field measurement techniques to ...supersonic flows yields three problems: low spatiotemporal resolution, limitation of measuring 3D density field, and low signal to noise ratio (SNR). A new method based on Nano-based Planar Laser Scattering (NPLS) technique is proposed in this paper to measure supersonic density field. This method measures planar transient density field in 3D supersonic flow by calibrating the relationship between density and concentration of tracer particles, which would display the density fluctuation due to the influence of shock waves and vortexes. The application of this new method to density field measurement of supersonic optical bow cap is introduced in this paper, and the results reveal shock wave, turbulent boundary layer in the flow with the spatial resolution of 93.2 μm/pixel. By analyzing the results at interval of 5 μs, temporal evolution of density field can be observed.
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