Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.
We identified two families ...with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells.
Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability.
This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.
In this study, we compared the response rates of blood, saliva, and buccal cell samples in a pilot study on the Danish nurse
cohort and examined the quantity and quality of the purified genomic DNA. ...Our data show that only 31% of the requested participants
delivered a blood sample, whereas 72%, 80%, and 76% delivered a saliva sample, buccal cell sample via mouth swabs, or buccal
cell sample on FTA card, respectively. Analysis of purified genomic DNA by NanoDrop and agarose gel electrophoresis revealed
that blood and saliva samples resulted in DNA with the best quality, whereas the DNA quality from buccal cells was low. Genotype
and PCR analysis showed that DNA from 100% of the blood samples and 72% to 84% of the saliva samples could be genotyped or
amplified, whereas none of the DNA from FTA cards and only 23% of the DNA from mouth swabs could be amplified and none of
the DNA from swabs and 94% of the DNA from FTA cards could be genotyped. Our study shows that the response rate of self-collection
saliva samples and buccal cell samples were much higher than the response rate of blood samples in our group of Danish nurses.
However, only the quality of genomic DNA from saliva samples was comparable with blood samples as accessed by purity, genotyping,
and PCR amplification. We conclude that the use of saliva samples is a good alternative to blood samples to obtain genomic
DNA of high quality and it will increase the response rate considerably in epidemiologic studies. (Cancer Epidemiol Biomarkers
Prev 2007;16(10):2072–6)
Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as ...several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes.
The In Salah CCS project in central Algeria is a world pioneering onshore CO2 capture and storage project which has built up a wealth of experience highly relevant to CCS projects worldwide. Carbon ...dioxide from several gas fields is removed from the gas production stream in a central gas processing facility and then the CO2 is compressed, transported and stored underground in the 1.9km deep Carboniferous sandstone unit at the Krechba field.
Injection commenced in 2004 and since then over 3.8Mt of CO2 has been stored in the subsurface. The storage performance has been monitored using a unique and diverse portfolio of geophysical and geochemical methods, including time-lapse seismic, micro-seismic, wellhead sampling using CO2 gas tracers, down-hole logging and core analysis, surface gas monitoring, groundwater aquifer monitoring and satellite InSAR data. Routines and procedures for collecting and interpreting these data have been developed, and valuable insights into appropriate Monitoring, Modelling and Verification (MMV) approaches for CO2 storage have been gained.
We summarize the key elements of the project life-cycle and identify the key lessons learned from this demonstration project that can be applied to other major CCS projects, notably:•The need for detailed geological and geomechanical characterization of the reservoir and overburden;•The importance of regular risk assessments based on the integration of multiple different datasets;•The importance of flexibility in the design and operation of the capture, compression, and injection system.
The In Salah project thus provides an important case study for knowledge transfer to other major CCS projects in the planning and execution phases.
We present a search at the Jefferson Laboratory for new forces mediated by sub-GeV vector bosons with weak coupling α' to electrons. Such a particle A' can be produced in electron-nucleus ...fixed-target scattering and then decay to an e + e- pair, producing a narrow resonance in the QED trident spectrum. Using APEX test run data, we searched in the mass range 175-250 MeV, found no evidence for an A'→ e+ e- reaction, and set an upper limit of α'/α ~/= 10(-6). Our findings demonstrate that fixed-target searches can explore a new, wide, and important range of masses and couplings for sub-GeV forces.
Microplastics (MPs) have become a global issue as they are omnipresent in the ocean. Fish ingesting MPs through feed could be affected in their physiological function, e.g., disrupted enzyme ...production and function, reduction of feeding and reproductive failure. This study assessed the effects of feed containing naturally weathered MPs from the Oslofjord (Norway) on the reproductive physiology of Atlantic cod (Gadus morhua). Farmed cod broodstock were fed either control (C-diet) or feeds containing 1% microplastic (MP-diet) starting nine months prior to spawning, from June until May. No major differences were found between diet groups in overall biometrics or gonad histology. Sex steroid levels (testosterone, 11-ketotestosterone and 17β-estradiol) resulted in expected profiles increasing over time without any significant differences between treatments. Gene expression levels of the steroidogenic enzyme 20β-hydroxysteroid dehydrogenase (20β-hsd) and vitellogenin1 (vtg1) showed significant differences between dietary treatments with lower expression in the control group. This can be a direct effect of MPs, but endocrine disrupting effects of potentially leachable plastic additives cannot be completely ruled out. Thus, these enzymes could be indicators of exposure to contaminants that disrupt sexual maturation by affecting the production of primarily maturation-inducing steroid. Although the concentration of MPs employed in this study may not be high enough to elicit any observable short-term biological effects, the observed gene expression suggests that long-term consequences should be considered caused by an expected increase of MPs in marine environments.
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•Dietary inclusion of 1% weathered PE had no effect on digestion or fish biometrics.•No dietary effect on gonadal development, fecundity or on egg quality were observed.•Gene expression through the BPG-axis and plasma steroid analysis was normal.•Gonadal and liver gene expressions of 20β-hsd and vtg1 differed between the groups.
The E12-14-012 experiment, performed in Jefferson Lab Hall A, has measured the $(e, e'p)$ cross section in parallel kinematics using a natural argon target. Here, we report the full results of the ...analysis of the data set corresponding to beam energy 2.222 GeV, and spanning the missing momentum and missing energy range $15 \lesssim p_m \lesssim 300$ MeV/c and $12 \lesssim E_m \lesssim 80$ MeV. The reduced cross section, determined as a function of $p_m$ and $E_m$ with $\approx$4\% accuracy, has been fitted using the results of Monte Carlo simulations involving a model spectral function and including the effects of final state interactions. The overall agreement between data and simulations turns out to be quite satisfactory ($\chi^2$/n.d.o.f.=1.9). Furthermore, the resulting spectral function will provide valuable new information, needed for the interpretation of neutrino interactions in liquid argon detectors.
To probe CP violation in the leptonic sector using GeV energy neutrino beams in current and future experiments using argon detectors, precise models of the complex underlying neutrino and ...antineutrino interactions are needed. The E12-14-012 experiment at Jefferson Lab Hall A was designed to perform a combined analysis of inclusive and exclusive electron scatterings on both argon (N = 22) and titanium (Z = 22) nuclei using GeV-energy electron beams. The measurement on titanium nucleus provides essential information to understand the neutrino scattering on argon, large contribution to which comes from scattering off neutrons. Here we report the first experimental study of electron-titanium scattering as double-differential cross section at beam energy E = 2.222 GeV and electron-scattering angle theta = 15.541 degrees, measured over a broad range of energy transfer, spanning the kinematical regions in which quasielastic scattering and delta production are the dominant reaction mechanisms. The data provide valuable new information needed to develop accurate theoretical models of the electromagnetic and weak cross sections of these complex nuclei in the kinematic regime of interest to neutrino experiments.
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