Curation and interpretation of copy number variants identified by genome-wide testing is challenged by the large number of events harbored in each personal genome. Conventional determination of ...phenotypic relevance relies on patterns of higher frequency in affected individuals versus controls; however, an increasing amount of ascertained variation is rare or private to clans. Consequently, frequency data have less utility to resolve pathogenic from benign. One solution is disease-specific algorithms that leverage gene knowledge together with variant frequency to aid prioritization. We used large-scale resources including Gene Ontology, protein-protein interactions and other annotation systems together with a broad set of 83 genes with known associations to epilepsy to construct a pathogenicity score for the phenotype. We evaluated the score for all annotated human genes and applied Bayesian methods to combine the derived pathogenicity score with frequency information from our diagnostic laboratory. Analysis determined Bayes factors and posterior distributions for each gene. We applied our method to subjects with abnormal chromosomal microarray results and confirmed epilepsy diagnoses gathered by electronic medical record review. Genes deleted in our subjects with epilepsy had significantly higher pathogenicity scores and Bayes factors compared to subjects referred for non-neurologic indications. We also applied our scores to identify a recently validated epilepsy gene in a complex genomic region and to reveal candidate genes for epilepsy. We propose a potential use in clinical decision support for our results in the context of genome-wide screening. Our approach demonstrates the utility of integrative data in medical genomics.
...we analysed available incubation period data of 512 confirmed cases from five EVD outbreaks from the last ten years and found that the mean and median incubation periods of the gamma distributions ...fitted to the cases was 10 days (SD 5·3 days). ...we performed a literature review of experimental infection in non-human primates, which found that 103 (98%) of 105 non-human primates injected with lethal doses of EBOV showed initial signs of illness 3 or more days after injection (appendix pp 5–6). ...epidemiological investigations of EVD outbreaks that encounter cases where the incubation period is suspected to be shorter than 4 days should clarify whether these cases and their suspected source patients share a common origin of infection (eg, common source patient) that had not been previously identified.
Current non-invasive prenatal screening is targeted toward the detection of chromosomal abnormalities in the fetus
. However, screening for many dominant monogenic disorders associated with de novo ...mutations is not available, despite their relatively high incidence
. Here we report on the development and validation of, and early clinical experience with, a new approach for non-invasive prenatal sequencing for a panel of causative genes for frequent dominant monogenic diseases. Cell-free DNA (cfDNA) extracted from maternal plasma was barcoded, enriched, and then analyzed by next-generation sequencing (NGS) for targeted regions. Low-level fetal variants were identified by a statistical analysis adjusted for NGS read count and fetal fraction. Pathogenic or likely pathogenic variants were confirmed by a secondary amplicon-based test on cfDNA. Clinical tests were performed on 422 pregnancies with or without abnormal ultrasound findings or family history. Follow-up studies on cases with available outcome results confirmed 20 true-positive, 127 true-negative, zero false-positive, and zero-false negative results. The initial clinical study demonstrated that this non-invasive test can provide valuable molecular information for the detection of a wide spectrum of dominant monogenic diseases, complementing current screening for aneuploidies or carrier screening for recessive disorders.
De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) ...phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the “CNV-mutator state,” and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.
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•Identification of a rare phenomenon, the multiple de novo CNV (MdnCNV) phenotype•MdnCNV arises in a perizygotic time interval, affecting all cells of a human body•MdnCNV favors formation of copy number gains•Imperfect microhomology and de novo mutations are found at the breakpoint junctions
Occurrence of multiple independent de novo copy number variants in individuals with developmental disorders points to a window in early development permissive to large-scale chromosomal rearrangements.
To further assess the scale and level of parental somatic mosaicism, we queried the CMA database at Baylor Genetics. We selected 50 unrelated families where clinically relevant apparent de novo ...CNV-deletions were found in the affected probands. Parental blood samples screening using deletion junction-specific PCR revealed four parents with somatic mosaicism. Droplet digital PCR (ddPCR), qPCR, and amplicon-based next-generation sequencing (NGS) were applied to validate these findings. Using ddPCR levels of mosaicism ranged from undetectable to 18.5%. Amplicon-based NGS and qPCR for the father with undetectable mosaicism was able to detect mosaicism at 0.39%. In one mother, ddPCR analysis revealed 15.6%, 10.6%, 8.2%, and undetectable levels of mosaicism in her blood, buccal cells, saliva, and urine samples, respectively. Our data suggest that more sensitive and precise methods, e.g. CNV junction-specific LR-PCR, ddPCR, or qPCR may allow for a more refined assessment of the potential disease recurrence risk for an identified variant.
•The scale and levels of low-level parental somatic mosaicism are incompletely understood.•We propose an approach for more effective detection of low-level parental somatic mosaicism for CNV deletions for a more accurate assessment and estimate of disease recurrence risk.
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