Prática de Shadowing: Presentation - Copy Number Variant Interpretation/Dosage Sensitivity Curation (Erica Andersen) - Aprenda a falar inglês com vídeo
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Hello, my name is Erica Anderson and today I'll be discussing resources used for clinical copy number variant or CNV interpretation.
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I'll review new metrics
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and reporting recommendations developed by our CNV interpretation guidelines committee as
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well as details on how to use our publicly available dosage sensitivity map.
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Resources relating to CNV interpretation are available on the conference website and will be covered in more detail during this workshop.
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I'd like to start by highlighting a couple of challenges to the CNV interpretation process.
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The first being that most CNVs are unique or non -recurrent and thus have variable breakpoints in gene content.
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This figure shows some examples of unique CNVs involving many genes, few genes, and no genes.
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During clinical encounter, evaluating each of these CNVs will involve compiling evidence from different resources,
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then using standardized processes to classify each appropriately, followed by tailoring the clinical report for any CNVs that meet your lab's reporting criteria.
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Recurrent CNVs, which, shown at the bottom, involve the same genomic content,
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collectively account for close to 10 % of CNVs encountered in frontline genomic testing.
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Such CNVs have been shown to associate with variable clinical findings and exhibit reduced penetrance,
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and thus also need to be classified and reported in a standardized way so their significance can be counseled appropriately.
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Another challenge for CNV interpretation is evaluating information relating to genes,
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as those that are disease associated may do so by mechanisms other than deletion or duplication or dosage sensitivity.
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For any particular gene, a variety of variant types may be observed.
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Some variants may be disease -causing and others benign, or some variants may cause different clinical phenotypes depending on the gene.
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This figure illustrates the complexity of the potential mutational spectrum that may be observed for individual genes.
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At the top, a number of disease -associating sequence variants may be reported in the literature,
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only some of which are likely to cause a complete loss of function, similar to a full gene deletion,
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and few, if any, will act similarly to a whole gene duplication.
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Additionally, CNVs both encompassing entire genes, partially overlapping, or occurring within them can have differing effects,
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and so gene level evaluation needs include compiling evidence from different resources,
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including both cytogenomic and molecular resources, understanding of technical limitations and functional effects of variants occurring within genes,
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as well as standardized classification processes.
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In order to improve these processes, a collaborative working group of the American College of Medical Genetics
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and Genomics and ClinGen developed updated technical standards published in late 2019, which I'll be taking you through today.
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For those of you familiar with genomic microarray testing,
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this new set of standards was built using the original 2011 ACMG guideline as a foundation
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and incorporates aspects of new frameworks developed analogously for sequence variant interpretation.
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Ultimately, these new guidelines aim to standardize classification and reporting practices across labs, technologies, and genetic specialties.
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To review these updated CNV technical standards, from the workshop page, click on our working group site,
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click on the technical standards, view citation, then view documents in PubMed Central,
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where you can access the manuscript as a PDF or full text, as well as download all of the supplemental materials.
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These include a very detailed user's guide, as well as example cases and reports.
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So next I'll provide an overview of the new features in these updated guidelines,
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the first of which was to officially adopt the five -tier variant classification system, which had been recommended for sequence variants since 2015.
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It involved separating CNVs classified as likely pathogenic and likely benign out from a primary uncertain category.
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The committee recommends using these standard classification terms for all CNV types in order to avoid confusion for clinicians and families.
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If caveats exist, additional information can be provided in the report text to further explain the result.
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Another major change was the development of a new numerical -based scoring system for CNVs, with separate scoring metrics developed for deletions and duplications.
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Key features of these new metrics include starting each CNV at a baseline of zero corresponding to uncertain or VUS,
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then requiring evidence to both up and downgrade CNV classifications.
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Each piece of evidence is evaluated based on its categorical strength
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and assigned a corresponding point score using categories intended to harmonize with those used for sequence variant interpretation.
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Default values are provided for all evidence types,
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but ranges are included for many categories to provide flexibility based on evidence strength within a category.
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Each CNV metric has the same five key evidence types evaluated, which are separated into different sections and scored independently.
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Section 1 involves assessing genomic content within the deleted
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or duplicated interval to determine if protein coding or other gene regulatory elements are present.
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In Section 2, the user determines whether and to what extent the CNV overlaps any established, dosage -sensitive, or benign genes or regions,
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using resources including the ClinGen dosage sensitivity map which I'll be going over shortly.
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A few highlights from this section are rules for intragenic CNV evaluation and HI predictors for deletions.
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section 3 involves a gene count within the cnv interval focusing on the total number of protein coding genes
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and there are rules for regions containing gene families different gene
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count thresholds are also designated for deletions versus duplications section 4
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is the most labor intensive section of the metric as here the user must identify similar cnvs to
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that under investigation and assign points for each reported case based on how specific the associated phenotype is,
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the inheritance pattern, and whether there is overlap with common variation or available case control data to evaluate.
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Finally, in Section 5, the user evaluates the associated phenotype and inheritance pattern for the CNV of the patient being studied.
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To assist users in working through these new metrics, ClinGen has developed a free web -based CNV calculator tool
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that you may access from the ClinGen website and in the materials provided today.
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From the main page, choose the appropriate scoring metric,
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evaluate gene content and whether established dosage -sensitive or benign regions are involved,
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checking to ensure the correct points category applies based on extent of CMV overlap,
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then evaluate protein coding gene count within the interval,
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followed by the detailed evidence evaluation assigning points for each reported proband from the literature using information including phenotype and inheritance patterns.
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In section 5, use the same rules for the patient being studied.
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The calculator will automatically assign a five -tier classification based on the total points scored.
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Scores for each evidence category are summed to a total value and assigned a corresponding classification.
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Pathogenic and benign are reached when beyond the plus or minus 0 .99 threshold.
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Likely pathogenic and likely benign are in a narrower range of plus or minus 0 .9 to 0 .98,
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while the VUS category is the broadest range from negative 0 .89 to 0 .89.
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The total point values were developed to correspond to confidence levels that a particular CNV is disease -causing or benign,
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similar to confidence measures suggested in the 2015 sequence variant interpretation guidelines,
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indicating pathogenic and benign should have a 99 % level of confidence of this classification,
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while likely pathogenic and likely benign should have at least a 90 % level of confidence of this classification.
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So now that you've learned the basics, let's go through an example case.
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Case 1 is a newborn male with poor feeding who is small for his gestational age.
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A genomic microarray was performed and identified an 882 kb deletion within chromosome 20p12 .2.
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Parental testing showed this deletion was de novo.
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Let's Let's take this deletion through the copy number loss metric.
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In the first step of the metric, we examine whether the deletion contains or does not contain protein coding or other functionally important elements.
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You can do this using annotations built into your software or using your favorite genome browser.
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Just remember to double check your input format and match the correct genome build.
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Here, I plug these coordinates into the UCSC genome browser and turn on the NCBI RefSeq genes track,
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which is showing about 9 genes in this region, some of which have multiple transcript isoforms.
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Of these genes, those that are protein coding are indicated with the NM underscore at the beginning of their transcript ID.
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We can see that five of these genes are protein coding,
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so we assign zero points to Section 1A and continue through the metric.
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If conversion of your query sequence to another genome build is needed, you can use tools such as the View
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and Other Genomes tool in UCSC to take coordinates from the current assembly and convert them into another, such as HG38.
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This can be used when sequence builds vary between platforms and resources available to investigate CNVs.
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Here, I converted an HG19 sequence to an HG38 in order to evaluate this CNV in the Decipher database.
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In Decipher, However, users can also find information, such as gene count, and how many genes are protein coding.
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In Section 2 of the CNV Interpretation Metrics,
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we must evaluate whether this multi -gene -encompassing deletion completely overlaps an established dosage -sensitive or benign gene or region,
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which would move scoring for this deletion into a pathogenic or benign category, respectively.
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In order to do this, we're going to first look at the ClinGen dosage sensitivity map, which is stated in the guidelines,
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specifically annotates and scores genes and genomic regions in relationship to dosage sensitivity, and should be used to interrogate most CNVs.
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The dosage map is curated by the ClinGen dosage sensitivity working group.
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In this working group, we aim to address this basic question,
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does loss or gain of a copy of a particular gene or genomic region result in a clinical phenotype?
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Similar to clinical C and B scoring, the ratings assigned for dosage sensitivity correspond to strengths of evidence.
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A 3 -score is the highest level of evidence, corresponding to sufficient evidence for pathogenicity.
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A 2 -score indicates there is some evidence for dosage sensitivity that is emerging.
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1 indicates little evidence and information is limited at this time.
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A 0 -score indicates that either no evidence exists or that evidence available is insufficient.
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And finally, the dosage sensitivity unlikely category indicates genes and regions for which there is evidence refuting dosage sensitivity.
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We also have a ranking for genes with autosomal recessive inheritance patterns.
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The dosage sensitivity curation process started back in 2011 as an effort of the ISCA, or International Standards for Sciogenomic Arrays Consortium.
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Since then, the group has undergone a number of changes, including to their name.
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Their curation processes have also evolved.
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For the past few years, FOCUS subgroups have been working to curate neurodevelopmental genes,
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recurrent CNVs in other genomic regions, and hereditary cancer genes.
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You can find more information about these subgroups' work on the Dosed Sensitivity Curation Group's website.
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The dosage map is curated by the ClinGen Dosed Sensitivity Working Group.
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You can visit our group page on the ClinGen site to
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learn more about our curation activities as well as to browse currently available curations.
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These curations include over 1400 genes in 72 regions scored for dosage sensitivity.
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You can review information on individual genes as well as genomic regions.
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And you can also input your own genomic coordinates from a CNV under investigation to evaluate our curated genomic content.
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But because this is a very recently updated feature, we're going to evaluate the CNV in case 1 using our legacy dosage map website,
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which now provides a link over to the updated site in ClinGen.
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On the main page, you can input either individual genes or genomic coordinates for CNV regions.
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Here, let's input the genomic coordinates for our deletion, double -checking the correct genome build is used.
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This takes you to a result page with tabs showing genes or regions that overlap our CNV.
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Here, two genes in the deleted region have been curated.
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One has a three score, the other is conferring recessive disease risk.
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On the right, you can click the link starting with ISCA to go to this genes page.
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The gene page includes curation status, date this gene was last evaluated, links out to other gene and disease resources,
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and the curated haploinsufficiency and triplo sensitivity scores with corresponding evidence summarized in the bottom tabs.
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Let's take a closer look at the information available for this gene.
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In the haploinsufficiency tab, you can see evidence relating to deletion and loss of function involving the gene JAG1.
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A three score is the highest level of evidence that deletion of this gene is disease -causing associated with Allergeal Syndrome.
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Historically, three patient reports were considered to provide sufficient evidence for dosage sensitivity,
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and so the current layout allows up to three references with links out to PubMed to be summarized here.
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Though this section is expanding with the updated website.
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At the bottom is a summary comment which typically includes information on the associated phenotype,
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mutational spectrum, genotype -phenotype associations, and inheritance, penetrance, and case control data,
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though not all three scored genes will contain this level of detail, particularly if the gene is already well known.
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This same information can be viewed on the new website in a slightly different format,
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with additional gene level information displayed at the top of the page.
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And so coming back to the classification metric,
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in section 2a we have identified an established haploid -sufficient gene that is fully contained by our patient's deletion.
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Therefore, this deletion will receive the max score of 1 in the metric.
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If you're following along using the calculator, this is what you should see.
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According to the metrics, in general, if a CNV reaches a 1
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or negative 1 score due to complete overlap with an established dosage -sensitive or benign gene or region,
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users of these metrics may not need to proceed further.
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And so with overlap with an established haplois -efficient gene, JAG1, our patient's deletion can be classified as pathogenic.
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However, it is important to point out that although we have a clinical classification, evaluating through the remainder of the metric may still be helpful
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to evaluate the potential phenotypic contribution of additional genes in the interval for genotype -phenotype correlation.
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In this study, the authors showed an association between deletion size and additional phenotypes seen in patients with Allergeal Syndrome,
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where deletions involving sequence outside of the black dotted lines were associated with additional phenotypes.
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Though our patient's deletion for case one, shown in red, is smaller than this interval,
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this type of information can still be useful to evaluate and note in the clinical report.
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So next we're going to return to the CMV Interpretation Guidelines Reporting Recommendations.
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Before we do so, I wanted to point out that on the Dosed Sensitivity Map website,
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we do have a list of useful files that can be downloaded from our FTP site.
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Here you can download several files containing lists of curated genes
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and regions which have been formatted for use in genome browsers as well as visualization software.
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Many of these files are updated daily.
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One track I'd like to highlight is the recurrent CNVs track shown here, displayed in the UCSC genome browser, showing the proximal 22q region.
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This region has a complex genomic architecture with an array of segmental duplications shown with the black bars
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that mediate recurrent deletions and duplications involving the orange regions,
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such as the common DeGeorge syndrome deletion involving the A to D segmental duplication regions.
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This track can be useful during genomic analysis to delineate these regions and find the appropriate literature to cite and evaluate,
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especially when dealing with some of the more rare rearrangements involving the central and distal regions.
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We also include links to the evidence curations for these regions on the dosage map site.
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Alongside CNV classification changes, another major change to the updated clinical CNV technical standards was to uncouple variant classification from clinical significance.
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This is because these are two different concepts.
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For CNV classification, we are asking whether there is enough evidence that the CNV under investigation causes disease.
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In determining clinical significance, however, we're asking whether the CNV is responsible for the phenotype of the patient being tested.
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For example, consider how you would classify and interpret the clinical significance for the following scenarios.
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First, a deletion of the recurrent 17p12 region containing the PMTP22 gene,
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which is responsible for a later onset motor and sensory neuropathy, called HMPP, observed in a newborn,
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referred for multiple congenital anomalies or an adult with foot drop.
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Next, consider how you would classify
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and interpret a deletion involving a gene on the X chromosome
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that causes an X -linked recessive cutaneous disorder in males
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that is observed in a 10 -year -old female referred for dysmorphism and severe intellectual disability and developmental delay.
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In both scenarios, the classification of the variant should remain the same.
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The evidence supporting these classifications at the same point in time is the same.
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Therefore, the variant should receive the same classification regardless of the context in which it was observed.
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In each scenario, the clinical significance of the variant could be different.
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In the first scenario, the variant could represent an incidental finding in one patient but explain the indication for testing in another.
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In the second scenario, the variant could be disease causing in a hemizygous male but represent a carrier state in a heterozygous female.
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Clearly labeled sections on a report delineating findings related to the reason for referral,
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findings that may be incidental and findings that may represent carrier status could be utilized to clarify these situations.
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In the supplemental materials provided with updated technical standards,
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we provide several example reports that illustrate how to communicate classification and interpretation for different scenarios.
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This example report describes a pathogenic CNV.
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Here, a deletion associated with progressive hearing loss identified in the workup for a child with developmental delay in autism. In this example,
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the report clearly states at the beginning
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that this test did not identify any variants that can explain the patient's reported clinical features,
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then follows to describe the pathogenic finding and its interpretation with respect to the clinical findings provided.
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Lower in the report are distinct CNV classification
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and relevance category fields to make this information clear to both the patient's family and clinician.
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The new technical standards included updates on the interpretation of secondary and incidental findings.
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During genomic testing, a CNV may be identified that involves a dosage -sensitive gene unrelated to the patient patient's reason for referral.
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Some examples include a large deletion causing syndromic features in a child that also includes a cancer risk gene,
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in this case BRCA1 in 17q,
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and a focal BRCA1 gene deletion identified in a fetal specimen referred for ultrasound anomalies.
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In both cases it would be important to highlight these findings
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as secondary in the patient's report for future medical management and possibly for familial counseling if inherited.
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The committee recommends reporting such CNVs if the mechanism of disease is consistent with haploinsufficiency or triplosensitivity.
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But be sure to consider the mechanism for pathogenicity as not all genes
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that have been annotated as associated with secondary or incidental findings cause disease due to dosage sensitivity.
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The ClinGen dosage sensitivity working group has a curated list of these genes
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that are targeted on the ACMG secondary findings list for sequence variants, which can be accessed from our webpage.
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The last change I'll discuss was also new compared to the 2011 guidance, which focused exclusively on postnatal CNV interpretation.
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In the update, the committee recommended to apply the classification metrics and evaluation process in the same manner for constitutional CNVs, regardless of context.
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Laboratories offering prenatal CNV testing are still allowed to set higher reporting thresholds if warranted, but should clearly state what those are.
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For example, only reporting pathogenic and likely pathic variants or only reporting VUS larger than a specific size threshold.
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So before moving on to our last case I
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wanted to highlight the CNV technical standards web series that's linked up at the top of this slide
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and also present in the materials that were provided to you all today.
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This web series was recorded this time last year actually
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over a nine -week period and covered a lot of the materials
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that I didn't have time to get into detail about today,
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including an overview on the technical standards that was provided by Erin Riggs,
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my colleague who's on the webinar with me today, a webinar devoted to the use of the ClinGen Dosed Sensitivity Map.
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We also covered how to score case -level data, considerations for evaluating intragenic CNVs,
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understanding case control data, using resources for population CNVs, both NOMAD
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and the database base of genomic variants more information on how
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to uncouple the variant classification from the clinical significance in the report
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and then we also did a Q &A session finally
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this past November several of us in the United States recorded our own experiences implementing the new guidelines
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which are available at the same web address linked above
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so let's look at another case case 2 is a
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three -year -old male referred for genomic microarray testing for developmental delay a deletion in chromosome 2q was identified
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and the inheritance is unknown
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if you want to follow along you can use the CNV loss metric as this deletion is indicated above.
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Starting again in section 1, a search of the deleted region here shown with the red
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bar shows a number of protein coding genes reside in this region.
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So section 1a would apply.
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Again in section 2 you need to determine whether this deletion
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or any genes within it are known to be dosage sensitive or benign.
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By plugging this region into the ClinGen dosage sensitivity map website, you can see that after sorting by haploinsufficiency score,
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there are no known HI genes in this region.
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We can move down to section 2H as there's no haploinsufficient genes in the region.
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Here, users are prompted to evaluate whether any genes in the region are predicted to be haploinsufficient.
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In order to assign points here,
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at least one gene within the deleted region must have both a high PLI score and a low HI index.
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To evaluate, you can query the region in the Decipher database and sort by these scores.
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Please keep in mind that the PLI scores are calculated in the NOMAD database.
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For this deletion, there are only two genes with a high PLI score, but they do not also have a low HI index,
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and so no points can be assigned in Section 2H.
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In Section 3, users should evaluate the number of protein -coding genes in the region.
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Here, I used the DecipherSearch tool to do this count by limiting my review to only protein -coding genes.
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Of the 23 genes in this deletion, 20 are protein -coding.
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So according to Section 3, the gene count is not high enough to score this deletion towards pathogenicity.
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So zero points is assigned in Section 3.
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Please note that since I made these slides,
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the Decipher database has been updated to exclusively display in HG38.
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So you'll have to follow the tutorial I provided earlier in order to convert your genomic coordinates to use Decipher today.
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Next, in section 4, we will need to do a detailed evaluation of this deletion using published literature,
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databases, and internal data, and looking for information including whether the deletion is de novo or inherited in the literature,
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whether it's segregating with inherited with clinical phenotypes,
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if associated clinical phenotypes are specific or nonspecific,
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and also whether deletions of this region are common in the general population or commonly inherited from relatives who are unaffected.
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But before we move on, let's go back to our dosage map search.
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For this deletion, there's actually a region curation that's been completed.
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So let's take a look at the information by clicking on the ISCA ID on the right.
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From here, you can see that this curation is complete, that it was updated in February of last year, and that the HI score is 1.
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Under the haplow insufficiency tab for this region, you can see the information that has been curated to arrive at a one score for haploid sufficiency.
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This information includes in the evidence section a literature summary which may include up to three references.
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In the comments section an explanation for the dosage score.
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For some entries a description of the genomic region may also be provided.
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An additional relevant literature such as case control data may also be included.
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The description section is used to provide additional information about the CNV.
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Here you can learn that this deletion is caused by recombination involving low copy repeats
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or seg dupes flanking this region in chromosome 2Q11 .2 and
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that genes within this region may be used to distinguish it from others nearby
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but are not necessarily the critical genes within this region.
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Coming back to this region in UCSC,
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we can now load up the recurrent CNVs track and observe where the unique sequence flanked by segmental duplication sequence resides.
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note that the breakpoints called may not perfectly align with the annotated region
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which generally corresponds to the innermost unique coordinates of the LCR
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blocks be sure to inspect the actual data for CNV calling in these regions to ensure
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you are dealing with the typical recurrent CNV.
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So, are we done yet?
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Based on a haploinsufficiency score of 1,
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the potential clinical classification for this deletion per the dosage sensitivity rankings is uncertain.
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However, as noted in the guidelines, for some CNVs, particularly those with incomplete penetrance or variable expressivity,
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additional evaluation may be necessary, and caution is recommended before interpreting a CNV based on this information alone.
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So let's take a look at the literature.
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After confirming no new literature exists,
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we can summarize the two studies that have been reported with the phenotypic association for deletions of this region, which were summarized in the ClinGen review.
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Between these two studies, five unrelated cases were identified identified.
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The phenotyping common across reported patients included speech delay,
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ADHD, dysmorphic features, and other variable features, which are generally nonspecific.
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And the inheritance patterns across these cases varied when known.
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In most cases, the deletion was inherited.
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Only one de novo case was reported.
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If we were to use this information to score these deletions in Section 4 of the metric,
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only one case would be counted in Section 4C for de novo evidence associated with a nonspecific phenotype,
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which would be given a default score of 0 .1.
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For the inherited cases, parental phenotype information was limited.
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Only the deletion of Subject 1 was noted to have been inherited from a father who had trouble in school.
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In order to score cases with parental inheritance in Sections 4F through H, at least three segregations must be established within a family,
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so we cannot count the deletion of Subject 1 in the metric.
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In the other cases, inheritance was maternal with no phenotypic information for subject 3,
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presumed based on two affected siblings but without further information for subjects 4 and 5,
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or for the case from 2009, the inheritance was unknown.
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According to the metric, only cases associated with the highly specific phenotype can be counted if the inheritance is unknown.
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Therefore, these additional cases would not be scored in section 4e.
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So to summarize, the 2Q11 .2 deletion has been reported in five cases in association with relatively nonspecific and variable clinical phenotypes.
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One case so far has been found to be de novo, giving this evidence 0 .1 points.
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Moving on to section 4L through O,
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let's take a look at the case control and population evidence for this deletion. For recurrent CNVs,
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one of the most comprehensive studies published by Koh et al
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in 2014 compared the frequencies of these cnvs in large clinical
316
and control populations in this study the 2q11 .2 deletion was observed in six cases and zero controls
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which gives a nominally significant p -value but low likelihood ratio that has wide confidence interval bounds.
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In another study of recurrent CNV frequency in a schizophrenia population, this deletion was observed in six cases versus one control,
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which gives both a high p -value and an odds ratio with wide confidence interval bounds.
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According to the CNV interpretation guidelines,
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CNVs counted in this category will be observed at a significantly higher frequency in cases versus controls, with a p -value less than 0 .05,
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and with a strong effect size, an odds ratio or likelihood ratio greater than 5,
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with a relatively narrow associated 95 % confidence interval, whose lower bound must be greater than 1.
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The statistical values for this region do not appear to satisfy these criteria.
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Coming back to the metric, for a deletion with a nonspecific phenotype, a maximum 0 .3 points per study could be assigned.
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But given the nominal significance estimates, we want to utilize the range of scores to downgrade the value of each of these studies.
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Here, I gave each study 0 .1 points for a total of 0 .2.
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Finally, in section 5 of the metric, we could consider the inheritance pattern for the deletion in our case, but here it is unknown,
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so no points could be assigned.
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Here we should note, as is stated in the guidelines, that special considerations may occur, particularly for regions like recurrent C and Vs,
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which may show incomplete penetrance and variable expressivity.
332
For example, in some cases, inheritance for a variant that is known to exhibit reduced penetrance may not be appropriate to score in Section 5.
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For this reason, along with other special considerations,
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the use of these metrics for classification of recurrent CNVs should be performed with caution,
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as a standardized classification system for these types of CNVs is still under development.
336
However, coming back to the 2Q11 .2 deletion,
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with limited evidence overall, the classification of this variant was calculated as VUS.
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This evidence corresponds to the one score provided in the Region Curation article on the Dosed Sensitivity Map website.
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Our goal in the Recurrent CNV subgroup is to continue to
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update Recurrent CNV curations using a scoring system analogous to the clinical CNV interpretation metric.
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We encourage users of the dosage map to contact us with feedback regarding specific gene
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or region reviews using the report information link on the gene and region page, or submit general questions, suggestions for gene or region reviews,
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and new evidence we should incorporate into our curations.
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I'd like to close by thanking my colleagues in the ACMG ClinGen CMV Interpretation Guidelines Committee,
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as well as the many wonderful members of our dosage sensitivity curation team.
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Please feel free to ask me questions or submit them in the chat.
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Vocabulário e dicas de fala para esta lição
Esta aula de conversação usa o vídeo “Presentation - Copy Number Variant Interpretation/Dosage Sensitivity Curation”. As palavras que mais se repetem: gene, cnv, deletion, region, section. Este vídeo tem 346 frases e 5089 palavras para praticar shadowing. A fala dura 42:06. O falante mantém um ritmo estável de cerca de 121 palavras por minuto, confortável para o shadowing. Apenas 72% das palavras estão entre as 3.000 mais comuns do inglês, por isso o vocabulário é exigente.
Vocabulário principal deste vídeo
15 palavras do vídeo que vale a pena aprender, com pronúncia e significado:
| Palavra | Pronúncia | Significado |
|---|---|---|
| gene substantivo | /d͡ʒiːn/ | gene |
| dosage substantivo | /ˈdəʊsɪd͡ʒ/ | dosagem |
| classification substantivo | /ˌklæsɪfɪˈkeɪʃən/ | classificação |
| metric adjetivo | /ˈmɛt.ɹɪk/ | métrico |
| variant substantivo | /ˈvæɹi.ənt/ | variante |
| evaluate verbo | /ɪˈvaljʊeɪt/ | avaliar |
| interpretation substantivo | /ɪnˌtɜːpɹəˈteɪʃən/ | interpretação |
| involve verbo | /ɪnˈvɑlv/ | envolver |
| inheritance substantivo | /ɪnˈhɛɹɪtəns/ | herança |
| benign adjetivo | /bɪˈnaɪn/ | benigno |
| sequence substantivo | /ˈsiː.kwəns/ | sequência |
| assign verbo | /əˈsaɪn/ | designar, atribuir |
| correspond verbo | /ˌkoɹəˈspɑnd/ | corresponder |
| observe verbo | /əbˈzɜːv/ | seguir, acompanhar |
| interval substantivo | /ˈɪntɚvəl/ | intervalo |
Phrasal verbs que você vai ouvir
| Palavra | Significado |
|---|---|
| point out verbo | apontar |
Gramática neste vídeo
As estruturas que o falante mais usa, com as palavras exatas do vídeo:
| Estrutura | No vídeo |
|---|---|
| Present perfect have/has + particípio passado — uma ação passada que ainda importa agora | have been shown · has developed · you've learned |
| Voz passiva be + particípio passado — o foco está no que acontece, não em quem faz | will be covered · have been shown · be classified |
| Orações relativas who / which + oração — informação extra sobre uma pessoa ou coisa | evaluated, which are · map, which is · regions which have |
Pronúncia para ficar de olho
O falante usa 17 contrações e formas reduzidas, como I'll, we're, I'd. Diga-as na forma curta, do jeito que você ouve.
- Os sons de “th”: threshold /ˈθɹɛʃ(h)oʊld/, pathogenic /pæθəˈd͡ʒɛnɪk/, pathogenicity /ˌpæθəd͡ʒəˈnɪsɪti/
- Os sons de “sh” e “zh”: classification /ˌklæsɪfɪˈkeɪʃən/, interpretation /ɪnˌtɜːpɹəˈteɪʃən/, evaluation /ɪˌvæljuˈeɪʃn̩/, ratio /ˈɹeɪ.ʃoʊ/, threshold /ˈθɹɛʃ(h)oʊld/
- Palavras longas — acerte a sílaba tônica: classification /ˌklæsɪfɪˈkeɪʃən/, sensitivity /ˌsɛn.səˈtɪv.ə.ti/, interpretation /ɪnˌtɜːpɹəˈteɪʃən/, inheritance /ɪnˈhɛɹɪtəns/, significance /sɪɡˈnɪfɪkəns/
Sons difíceis para falantes de português:
- Consoante final — sem acrescentar um “i” depois: metric /ˈmɛt.ɹɪk/, variant /ˈvæɹi.ənt/, evaluate /ɪˈvaljʊeɪt/, correspond /ˌkoɹəˈspɑnd/, coordinate /koʊˈɔɹ.dəˌneɪt/
- /l/ final — a língua toca o céu da boca, não vira “u”: interval /ˈɪntɚvəl/, developmental /dɪˌvɛləpˈmɛntəl/, parental /pəˈɹɛn.təl/, referral /ɹɪˈfɜː.ɹəl/, constitutional /ˌkɒn.stɪˈtjuː.ʃ(ə)n.(ə)l/
- /h/ — um sopro suave, diferente do “r”: inheritance /ɪnˈhɛɹɪtəns/, inherit /ɪnˈhɛɹɪt/, threshold /ˈθɹɛʃ(h)oʊld/, highlight /ˈhaɪˌlaɪt/, likelihood /ˈlaɪklihʊd/
Como praticar com este vídeo
- Ouça o vídeo inteiro uma vez sem falar e anote as palavras que você não conhece.
- Faça shadowing frase por frase na velocidade normal, repetindo cada uma até o seu ritmo ficar igual ao do falante.
- Grave a sua voz e compare com o original, prestando atenção a palavras como gene, dosage, classification.
O que é a Técnica de Shadowing?
Shadowing é uma técnica de aprendizado de idiomas com base científica, originalmente desenvolvida para o treinamento de intérpretes profissionais. O método é simples, mas poderoso: você ouve áudio em inglês nativo e repete imediatamente em voz alta — como uma sombra seguindo o falante com 1-2 segundos de atraso. Pesquisas mostram melhora significativa na precisão da pronúncia, entonação, ritmo, sons conectados, compreensão auditiva e fluência na fala.