Практика Shadowing: Presentation - Copy Number Variant Interpretation/Dosage Sensitivity Curation (Erica Andersen) - Изучайте разговорный английский по видео

Выберите режим практики

Каждый режим открывает полноэкранную комнату практики.

346 предложений

Если предложения слишком короткие или длинные, нажмите Edit, чтобы их изменить.

Hello, my name is Erica Anderson and today I'll be discussing resources used for clinical copy number variant or CNV interpretation.

I'll review new metrics

and reporting recommendations developed by our CNV interpretation guidelines committee as

well as details on how to use our publicly available dosage sensitivity map.

Resources relating to CNV interpretation are available on the conference website and will be covered in more detail during this workshop.

I'd like to start by highlighting a couple of challenges to the CNV interpretation process.

The first being that most CNVs are unique or non -recurrent and thus have variable breakpoints in gene content.

This figure shows some examples of unique CNVs involving many genes, few genes, and no genes.

During clinical encounter, evaluating each of these CNVs will involve compiling evidence from different resources,

then using standardized processes to classify each appropriately, followed by tailoring the clinical report for any CNVs that meet your lab's reporting criteria.

Recurrent CNVs, which, shown at the bottom, involve the same genomic content,

collectively account for close to 10 % of CNVs encountered in frontline genomic testing.

Such CNVs have been shown to associate with variable clinical findings and exhibit reduced penetrance,

and thus also need to be classified and reported in a standardized way so their significance can be counseled appropriately.

Another challenge for CNV interpretation is evaluating information relating to genes,

as those that are disease associated may do so by mechanisms other than deletion or duplication or dosage sensitivity.

For any particular gene, a variety of variant types may be observed.

Some variants may be disease -causing and others benign, or some variants may cause different clinical phenotypes depending on the gene.

This figure illustrates the complexity of the potential mutational spectrum that may be observed for individual genes.

At the top, a number of disease -associating sequence variants may be reported in the literature,

only some of which are likely to cause a complete loss of function, similar to a full gene deletion,

and few, if any, will act similarly to a whole gene duplication.

Additionally, CNVs both encompassing entire genes, partially overlapping, or occurring within them can have differing effects,

and so gene level evaluation needs include compiling evidence from different resources,

including both cytogenomic and molecular resources, understanding of technical limitations and functional effects of variants occurring within genes,

as well as standardized classification processes.

In order to improve these processes, a collaborative working group of the American College of Medical Genetics

and Genomics and ClinGen developed updated technical standards published in late 2019, which I'll be taking you through today.

For those of you familiar with genomic microarray testing,

this new set of standards was built using the original 2011 ACMG guideline as a foundation

and incorporates aspects of new frameworks developed analogously for sequence variant interpretation.

Ultimately, these new guidelines aim to standardize classification and reporting practices across labs, technologies, and genetic specialties.

To review these updated CNV technical standards, from the workshop page, click on our working group site,

click on the technical standards, view citation, then view documents in PubMed Central,

where you can access the manuscript as a PDF or full text, as well as download all of the supplemental materials.

These include a very detailed user's guide, as well as example cases and reports.

So next I'll provide an overview of the new features in these updated guidelines,

the first of which was to officially adopt the five -tier variant classification system, which had been recommended for sequence variants since 2015.

It involved separating CNVs classified as likely pathogenic and likely benign out from a primary uncertain category.

The committee recommends using these standard classification terms for all CNV types in order to avoid confusion for clinicians and families.

If caveats exist, additional information can be provided in the report text to further explain the result.

Another major change was the development of a new numerical -based scoring system for CNVs, with separate scoring metrics developed for deletions and duplications.

Key features of these new metrics include starting each CNV at a baseline of zero corresponding to uncertain or VUS,

then requiring evidence to both up and downgrade CNV classifications.

Each piece of evidence is evaluated based on its categorical strength

and assigned a corresponding point score using categories intended to harmonize with those used for sequence variant interpretation.

Default values are provided for all evidence types,

but ranges are included for many categories to provide flexibility based on evidence strength within a category.

Each CNV metric has the same five key evidence types evaluated, which are separated into different sections and scored independently.

Section 1 involves assessing genomic content within the deleted

or duplicated interval to determine if protein coding or other gene regulatory elements are present.

In Section 2, the user determines whether and to what extent the CNV overlaps any established, dosage -sensitive, or benign genes or regions,

using resources including the ClinGen dosage sensitivity map which I'll be going over shortly.

A few highlights from this section are rules for intragenic CNV evaluation and HI predictors for deletions.

section 3 involves a gene count within the cnv interval focusing on the total number of protein coding genes

and there are rules for regions containing gene families different gene

count thresholds are also designated for deletions versus duplications section 4

is the most labor intensive section of the metric as here the user must identify similar cnvs to

that under investigation and assign points for each reported case based on how specific the associated phenotype is,

the inheritance pattern, and whether there is overlap with common variation or available case control data to evaluate.

Finally, in Section 5, the user evaluates the associated phenotype and inheritance pattern for the CNV of the patient being studied.

To assist users in working through these new metrics, ClinGen has developed a free web -based CNV calculator tool

that you may access from the ClinGen website and in the materials provided today.

From the main page, choose the appropriate scoring metric,

evaluate gene content and whether established dosage -sensitive or benign regions are involved,

checking to ensure the correct points category applies based on extent of CMV overlap,

then evaluate protein coding gene count within the interval,

followed by the detailed evidence evaluation assigning points for each reported proband from the literature using information including phenotype and inheritance patterns.

In section 5, use the same rules for the patient being studied.

The calculator will automatically assign a five -tier classification based on the total points scored.

Scores for each evidence category are summed to a total value and assigned a corresponding classification.

Pathogenic and benign are reached when beyond the plus or minus 0 .99 threshold.

Likely pathogenic and likely benign are in a narrower range of plus or minus 0 .9 to 0 .98,

while the VUS category is the broadest range from negative 0 .89 to 0 .89.

The total point values were developed to correspond to confidence levels that a particular CNV is disease -causing or benign,

similar to confidence measures suggested in the 2015 sequence variant interpretation guidelines,

indicating pathogenic and benign should have a 99 % level of confidence of this classification,

while likely pathogenic and likely benign should have at least a 90 % level of confidence of this classification.

So now that you've learned the basics, let's go through an example case.

Case 1 is a newborn male with poor feeding who is small for his gestational age.

A genomic microarray was performed and identified an 882 kb deletion within chromosome 20p12 .2.

Parental testing showed this deletion was de novo.

Let's Let's take this deletion through the copy number loss metric.

In the first step of the metric, we examine whether the deletion contains or does not contain protein coding or other functionally important elements.

You can do this using annotations built into your software or using your favorite genome browser.

Just remember to double check your input format and match the correct genome build.

Here, I plug these coordinates into the UCSC genome browser and turn on the NCBI RefSeq genes track,

which is showing about 9 genes in this region, some of which have multiple transcript isoforms.

Of these genes, those that are protein coding are indicated with the NM underscore at the beginning of their transcript ID.

We can see that five of these genes are protein coding,

so we assign zero points to Section 1A and continue through the metric.

If conversion of your query sequence to another genome build is needed, you can use tools such as the View

and Other Genomes tool in UCSC to take coordinates from the current assembly and convert them into another, such as HG38.

This can be used when sequence builds vary between platforms and resources available to investigate CNVs.

Here, I converted an HG19 sequence to an HG38 in order to evaluate this CNV in the Decipher database.

In Decipher, However, users can also find information, such as gene count, and how many genes are protein coding.

In Section 2 of the CNV Interpretation Metrics,

we must evaluate whether this multi -gene -encompassing deletion completely overlaps an established dosage -sensitive or benign gene or region,

which would move scoring for this deletion into a pathogenic or benign category, respectively.

100

In order to do this, we're going to first look at the ClinGen dosage sensitivity map, which is stated in the guidelines,

101

specifically annotates and scores genes and genomic regions in relationship to dosage sensitivity, and should be used to interrogate most CNVs.

102

The dosage map is curated by the ClinGen dosage sensitivity working group.

103

In this working group, we aim to address this basic question,

104

does loss or gain of a copy of a particular gene or genomic region result in a clinical phenotype?

105

Similar to clinical C and B scoring, the ratings assigned for dosage sensitivity correspond to strengths of evidence.

106

A 3 -score is the highest level of evidence, corresponding to sufficient evidence for pathogenicity.

107

A 2 -score indicates there is some evidence for dosage sensitivity that is emerging.

108

1 indicates little evidence and information is limited at this time.

109

A 0 -score indicates that either no evidence exists or that evidence available is insufficient.

110

And finally, the dosage sensitivity unlikely category indicates genes and regions for which there is evidence refuting dosage sensitivity.

111

We also have a ranking for genes with autosomal recessive inheritance patterns.

112

The dosage sensitivity curation process started back in 2011 as an effort of the ISCA, or International Standards for Sciogenomic Arrays Consortium.

113

Since then, the group has undergone a number of changes, including to their name.

114

Their curation processes have also evolved.

115

For the past few years, FOCUS subgroups have been working to curate neurodevelopmental genes,

116

recurrent CNVs in other genomic regions, and hereditary cancer genes.

117

You can find more information about these subgroups' work on the Dosed Sensitivity Curation Group's website.

118

The dosage map is curated by the ClinGen Dosed Sensitivity Working Group.

119

You can visit our group page on the ClinGen site to

120

learn more about our curation activities as well as to browse currently available curations.

121

These curations include over 1400 genes in 72 regions scored for dosage sensitivity.

122

You can review information on individual genes as well as genomic regions.

123

And you can also input your own genomic coordinates from a CNV under investigation to evaluate our curated genomic content.

124

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,

125

which now provides a link over to the updated site in ClinGen.

126

On the main page, you can input either individual genes or genomic coordinates for CNV regions.

127

Here, let's input the genomic coordinates for our deletion, double -checking the correct genome build is used.

128

This takes you to a result page with tabs showing genes or regions that overlap our CNV.

129

Here, two genes in the deleted region have been curated.

130

One has a three score, the other is conferring recessive disease risk.

131

On the right, you can click the link starting with ISCA to go to this genes page.

132

The gene page includes curation status, date this gene was last evaluated, links out to other gene and disease resources,

133

and the curated haploinsufficiency and triplo sensitivity scores with corresponding evidence summarized in the bottom tabs.

134

Let's take a closer look at the information available for this gene.

135

In the haploinsufficiency tab, you can see evidence relating to deletion and loss of function involving the gene JAG1.

136

A three score is the highest level of evidence that deletion of this gene is disease -causing associated with Allergeal Syndrome.

137

Historically, three patient reports were considered to provide sufficient evidence for dosage sensitivity,

138

and so the current layout allows up to three references with links out to PubMed to be summarized here.

139

Though this section is expanding with the updated website.

140

At the bottom is a summary comment which typically includes information on the associated phenotype,

141

mutational spectrum, genotype -phenotype associations, and inheritance, penetrance, and case control data,

142

though not all three scored genes will contain this level of detail, particularly if the gene is already well known.

143

This same information can be viewed on the new website in a slightly different format,

144

with additional gene level information displayed at the top of the page.

145

And so coming back to the classification metric,

146

in section 2a we have identified an established haploid -sufficient gene that is fully contained by our patient's deletion.

147

Therefore, this deletion will receive the max score of 1 in the metric.

148

If you're following along using the calculator, this is what you should see.

149

According to the metrics, in general, if a CNV reaches a 1

150

or negative 1 score due to complete overlap with an established dosage -sensitive or benign gene or region,

151

users of these metrics may not need to proceed further.

152

And so with overlap with an established haplois -efficient gene, JAG1, our patient's deletion can be classified as pathogenic.

153

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

154

to evaluate the potential phenotypic contribution of additional genes in the interval for genotype -phenotype correlation.

155

In this study, the authors showed an association between deletion size and additional phenotypes seen in patients with Allergeal Syndrome,

156

where deletions involving sequence outside of the black dotted lines were associated with additional phenotypes.

157

Though our patient's deletion for case one, shown in red, is smaller than this interval,

158

this type of information can still be useful to evaluate and note in the clinical report.

159

So next we're going to return to the CMV Interpretation Guidelines Reporting Recommendations.

160

Before we do so, I wanted to point out that on the Dosed Sensitivity Map website,

161

we do have a list of useful files that can be downloaded from our FTP site.

162

Here you can download several files containing lists of curated genes

163

and regions which have been formatted for use in genome browsers as well as visualization software.

164

Many of these files are updated daily.

165

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.

166

This region has a complex genomic architecture with an array of segmental duplications shown with the black bars

167

that mediate recurrent deletions and duplications involving the orange regions,

168

such as the common DeGeorge syndrome deletion involving the A to D segmental duplication regions.

169

This track can be useful during genomic analysis to delineate these regions and find the appropriate literature to cite and evaluate,

170

especially when dealing with some of the more rare rearrangements involving the central and distal regions.

171

We also include links to the evidence curations for these regions on the dosage map site.

172

Alongside CNV classification changes, another major change to the updated clinical CNV technical standards was to uncouple variant classification from clinical significance.

173

This is because these are two different concepts.

174

For CNV classification, we are asking whether there is enough evidence that the CNV under investigation causes disease.

175

In determining clinical significance, however, we're asking whether the CNV is responsible for the phenotype of the patient being tested.

176

For example, consider how you would classify and interpret the clinical significance for the following scenarios.

177

First, a deletion of the recurrent 17p12 region containing the PMTP22 gene,

178

which is responsible for a later onset motor and sensory neuropathy, called HMPP, observed in a newborn,

179

referred for multiple congenital anomalies or an adult with foot drop.

180

Next, consider how you would classify

181

and interpret a deletion involving a gene on the X chromosome

182

that causes an X -linked recessive cutaneous disorder in males

183

that is observed in a 10 -year -old female referred for dysmorphism and severe intellectual disability and developmental delay.

184

In both scenarios, the classification of the variant should remain the same.

185

The evidence supporting these classifications at the same point in time is the same.

186

Therefore, the variant should receive the same classification regardless of the context in which it was observed.

187

In each scenario, the clinical significance of the variant could be different.

188

In the first scenario, the variant could represent an incidental finding in one patient but explain the indication for testing in another.

189

In the second scenario, the variant could be disease causing in a hemizygous male but represent a carrier state in a heterozygous female.

190

Clearly labeled sections on a report delineating findings related to the reason for referral,

191

findings that may be incidental and findings that may represent carrier status could be utilized to clarify these situations.

192

In the supplemental materials provided with updated technical standards,

193

we provide several example reports that illustrate how to communicate classification and interpretation for different scenarios.

194

This example report describes a pathogenic CNV.

195

Here, a deletion associated with progressive hearing loss identified in the workup for a child with developmental delay in autism. In this example,

196

the report clearly states at the beginning

197

that this test did not identify any variants that can explain the patient's reported clinical features,

198

then follows to describe the pathogenic finding and its interpretation with respect to the clinical findings provided.

199

Lower in the report are distinct CNV classification

200

and relevance category fields to make this information clear to both the patient's family and clinician.

201

The new technical standards included updates on the interpretation of secondary and incidental findings.

202

During genomic testing, a CNV may be identified that involves a dosage -sensitive gene unrelated to the patient patient's reason for referral.

203

Some examples include a large deletion causing syndromic features in a child that also includes a cancer risk gene,

204

in this case BRCA1 in 17q,

205

and a focal BRCA1 gene deletion identified in a fetal specimen referred for ultrasound anomalies.

206

In both cases it would be important to highlight these findings

207

as secondary in the patient's report for future medical management and possibly for familial counseling if inherited.

208

The committee recommends reporting such CNVs if the mechanism of disease is consistent with haploinsufficiency or triplosensitivity.

209

But be sure to consider the mechanism for pathogenicity as not all genes

210

that have been annotated as associated with secondary or incidental findings cause disease due to dosage sensitivity.

211

The ClinGen dosage sensitivity working group has a curated list of these genes

212

that are targeted on the ACMG secondary findings list for sequence variants, which can be accessed from our webpage.

213

The last change I'll discuss was also new compared to the 2011 guidance, which focused exclusively on postnatal CNV interpretation.

214

In the update, the committee recommended to apply the classification metrics and evaluation process in the same manner for constitutional CNVs, regardless of context.

215

Laboratories offering prenatal CNV testing are still allowed to set higher reporting thresholds if warranted, but should clearly state what those are.

216

For example, only reporting pathogenic and likely pathic variants or only reporting VUS larger than a specific size threshold.

217

So before moving on to our last case I

218

wanted to highlight the CNV technical standards web series that's linked up at the top of this slide

219

and also present in the materials that were provided to you all today.

220

This web series was recorded this time last year actually

221

over a nine -week period and covered a lot of the materials

222

that I didn't have time to get into detail about today,

223

including an overview on the technical standards that was provided by Erin Riggs,

224

my colleague who's on the webinar with me today, a webinar devoted to the use of the ClinGen Dosed Sensitivity Map.

225

We also covered how to score case -level data, considerations for evaluating intragenic CNVs,

226

understanding case control data, using resources for population CNVs, both NOMAD

227

and the database base of genomic variants more information on how

228

to uncouple the variant classification from the clinical significance in the report

229

and then we also did a Q &A session finally

230

this past November several of us in the United States recorded our own experiences implementing the new guidelines

231

which are available at the same web address linked above

232

so let's look at another case case 2 is a

233

three -year -old male referred for genomic microarray testing for developmental delay a deletion in chromosome 2q was identified

234

and the inheritance is unknown

235

if you want to follow along you can use the CNV loss metric as this deletion is indicated above.

236

Starting again in section 1, a search of the deleted region here shown with the red

237

bar shows a number of protein coding genes reside in this region.

238

So section 1a would apply.

239

Again in section 2 you need to determine whether this deletion

240

or any genes within it are known to be dosage sensitive or benign.

241

By plugging this region into the ClinGen dosage sensitivity map website, you can see that after sorting by haploinsufficiency score,

242

there are no known HI genes in this region.

243

We can move down to section 2H as there's no haploinsufficient genes in the region.

244

Here, users are prompted to evaluate whether any genes in the region are predicted to be haploinsufficient.

245

In order to assign points here,

246

at least one gene within the deleted region must have both a high PLI score and a low HI index.

247

To evaluate, you can query the region in the Decipher database and sort by these scores.

248

Please keep in mind that the PLI scores are calculated in the NOMAD database.

249

For this deletion, there are only two genes with a high PLI score, but they do not also have a low HI index,

250

and so no points can be assigned in Section 2H.

251

In Section 3, users should evaluate the number of protein -coding genes in the region.

252

Here, I used the DecipherSearch tool to do this count by limiting my review to only protein -coding genes.

253

Of the 23 genes in this deletion, 20 are protein -coding.

254

So according to Section 3, the gene count is not high enough to score this deletion towards pathogenicity.

255

So zero points is assigned in Section 3.

256

Please note that since I made these slides,

257

the Decipher database has been updated to exclusively display in HG38.

258

So you'll have to follow the tutorial I provided earlier in order to convert your genomic coordinates to use Decipher today.

259

Next, in section 4, we will need to do a detailed evaluation of this deletion using published literature,

260

databases, and internal data, and looking for information including whether the deletion is de novo or inherited in the literature,

261

whether it's segregating with inherited with clinical phenotypes,

262

if associated clinical phenotypes are specific or nonspecific,

263

and also whether deletions of this region are common in the general population or commonly inherited from relatives who are unaffected.

264

But before we move on, let's go back to our dosage map search.

265

For this deletion, there's actually a region curation that's been completed.

266

So let's take a look at the information by clicking on the ISCA ID on the right.

267

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.

268

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.

269

This information includes in the evidence section a literature summary which may include up to three references.

270

In the comments section an explanation for the dosage score.

271

For some entries a description of the genomic region may also be provided.

272

An additional relevant literature such as case control data may also be included.

273

The description section is used to provide additional information about the CNV.

274

Here you can learn that this deletion is caused by recombination involving low copy repeats

275

or seg dupes flanking this region in chromosome 2Q11 .2 and

276

that genes within this region may be used to distinguish it from others nearby

277

but are not necessarily the critical genes within this region.

278

Coming back to this region in UCSC,

279

we can now load up the recurrent CNVs track and observe where the unique sequence flanked by segmental duplication sequence resides.

280

note that the breakpoints called may not perfectly align with the annotated region

281

which generally corresponds to the innermost unique coordinates of the LCR

282

blocks be sure to inspect the actual data for CNV calling in these regions to ensure

283

you are dealing with the typical recurrent CNV.

284

So, are we done yet?

285

Based on a haploinsufficiency score of 1,

286

the potential clinical classification for this deletion per the dosage sensitivity rankings is uncertain.

287

However, as noted in the guidelines, for some CNVs, particularly those with incomplete penetrance or variable expressivity,

288

additional evaluation may be necessary, and caution is recommended before interpreting a CNV based on this information alone.

289

So let's take a look at the literature.

290

After confirming no new literature exists,

291

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.

292

Between these two studies, five unrelated cases were identified identified.

293

The phenotyping common across reported patients included speech delay,

294

ADHD, dysmorphic features, and other variable features, which are generally nonspecific.

295

And the inheritance patterns across these cases varied when known.

296

In most cases, the deletion was inherited.

297

Only one de novo case was reported.

298

If we were to use this information to score these deletions in Section 4 of the metric,

299

only one case would be counted in Section 4C for de novo evidence associated with a nonspecific phenotype,

300

which would be given a default score of 0 .1.

301

For the inherited cases, parental phenotype information was limited.

302

Only the deletion of Subject 1 was noted to have been inherited from a father who had trouble in school.

303

In order to score cases with parental inheritance in Sections 4F through H, at least three segregations must be established within a family,

304

so we cannot count the deletion of Subject 1 in the metric.

305

In the other cases, inheritance was maternal with no phenotypic information for subject 3,

306

presumed based on two affected siblings but without further information for subjects 4 and 5,

307

or for the case from 2009, the inheritance was unknown.

308

According to the metric, only cases associated with the highly specific phenotype can be counted if the inheritance is unknown.

309

Therefore, these additional cases would not be scored in section 4e.

310

So to summarize, the 2Q11 .2 deletion has been reported in five cases in association with relatively nonspecific and variable clinical phenotypes.

311

One case so far has been found to be de novo, giving this evidence 0 .1 points.

312

Moving on to section 4L through O,

313

let's take a look at the case control and population evidence for this deletion. For recurrent CNVs,

314

one of the most comprehensive studies published by Koh et al

315

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

317

which gives a nominally significant p -value but low likelihood ratio that has wide confidence interval bounds.

318

In another study of recurrent CNV frequency in a schizophrenia population, this deletion was observed in six cases versus one control,

319

which gives both a high p -value and an odds ratio with wide confidence interval bounds.

320

According to the CNV interpretation guidelines,

321

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,

322

and with a strong effect size, an odds ratio or likelihood ratio greater than 5,

323

with a relatively narrow associated 95 % confidence interval, whose lower bound must be greater than 1.

324

The statistical values for this region do not appear to satisfy these criteria.

325

Coming back to the metric, for a deletion with a nonspecific phenotype, a maximum 0 .3 points per study could be assigned.

326

But given the nominal significance estimates, we want to utilize the range of scores to downgrade the value of each of these studies.

327

Here, I gave each study 0 .1 points for a total of 0 .2.

328

Finally, in section 5 of the metric, we could consider the inheritance pattern for the deletion in our case, but here it is unknown,

329

so no points could be assigned.

330

Here we should note, as is stated in the guidelines, that special considerations may occur, particularly for regions like recurrent C and Vs,

331

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.

333

For this reason, along with other special considerations,

334

the use of these metrics for classification of recurrent CNVs should be performed with caution,

335

as a standardized classification system for these types of CNVs is still under development.

336

However, coming back to the 2Q11 .2 deletion,

337

with limited evidence overall, the classification of this variant was calculated as VUS.

338

This evidence corresponds to the one score provided in the Region Curation article on the Dosed Sensitivity Map website.

339

Our goal in the Recurrent CNV subgroup is to continue to

340

update Recurrent CNV curations using a scoring system analogous to the clinical CNV interpretation metric.

341

We encourage users of the dosage map to contact us with feedback regarding specific gene

342

or region reviews using the report information link on the gene and region page, or submit general questions, suggestions for gene or region reviews,

343

and new evidence we should incorporate into our curations.

344

I'd like to close by thanking my colleagues in the ACMG ClinGen CMV Interpretation Guidelines Committee,

345

as well as the many wonderful members of our dosage sensitivity curation team.

346

Please feel free to ask me questions or submit them in the chat.

Скачать приложение

Всё для свободной речи

ИИ-оценка произношенияОценка каждой фразы

Практика IPAОсвойте каждый звук

СловарьСоберите свой словарный запас

Игра со словамиУчитесь играя

Сканировать QR

Download on theApp Store Get it onGoogle Play

Тот же канал

Sequence Variant Literature Search Tips and Tricks

Daily ConversationUniversity Students

FOR YOU

Лексика и советы по произношению к этому уроку

Этот урок разговорной практики построен на видео «Presentation - Copy Number Variant Interpretation/Dosage Sensitivity Curation». Чаще всего повторяются слова: gene, cnv, deletion, region, section. В этом видео 346 предложений и 5089 слов для шедоуинга. Речь длится 42:06. Говорящий держит ровный темп — около 121 слов в минуту, удобный для шедоуинга. Только 72% слов входят в 3000 самых частых слов английского языка, поэтому лексика сложная.

Ключевая лексика этого видео

15 слов из видео, которые стоит выучить, с произношением и значением:

Слово	Произношение	Значение
gene существительное	/d͡ʒiːn/	ген
dosage существительное	/ˈdəʊsɪd͡ʒ/	до́за, дозиро́вка
classification существительное	/ˌklæsɪfɪˈkeɪʃən/	классифика́ция, классифици́рование
metric прилагательное	/ˈmɛt.ɹɪk/	метри́ческий
sensitivity существительное	/ˌsɛn.səˈtɪv.ə.ti/	чувстви́тельность
variant существительное	/ˈvæɹi.ənt/	вариа́нт
evaluate глагол	/ɪˈvaljʊeɪt/	оце́нивать, оцени́ть
interpretation существительное	/ɪnˌtɜːpɹəˈteɪʃən/	перево́д, интерпрета́ция
involve глагол	/ɪnˈvɑlv/	каса́ться, косну́ться
inheritance существительное	/ɪnˈhɛɹɪtəns/	насле́дование
benign прилагательное	/bɪˈnaɪn/	до́брый, любе́зный
sequence существительное	/ˈsiː.kwəns/	после́довательность, ряд
assign глагол	/əˈsaɪn/	назнача́ть, назна́чить
correspond глагол	/ˌkoɹəˈspɑnd/	соотве́тствовать, согласо́вываться
observe глагол	/əbˈzɜːv/	соблюда́ть, блюсти́

Фразовые глаголы, которые вы услышите

Слово	Значение
point out глагол	ука́зывать, указа́ть

Грамматика в этом видео

Конструкции, которые говорящий использует чаще всего, с точными словами из видео:

Конструкция	В видео
Present Perfect have/has + причастие прошедшего времени — прошлое действие, важное сейчас	have been shown · has developed · you've learned
Пассивный залог be + причастие прошедшего времени — важно, что происходит, а не кто это делает	will be covered · have been shown · be classified
Придаточные определительные who / which + предложение — уточнение о человеке или предмете	evaluated, which are · map, which is · regions which have

Произношение, на которое стоит обратить внимание

Говорящий использует 17 сокращённых и редуцированных форм, например I'll, we're, I'd. Произносите их коротко, так, как слышите.

Звуки «th»: threshold /ˈθɹɛʃ(h)oʊld/, pathogenic /pæθəˈd͡ʒɛnɪk/, pathogenicity /ˌpæθəd͡ʒəˈnɪsɪti/
Звуки «sh» и «zh»: classification /ˌklæsɪfɪˈkeɪʃən/, interpretation /ɪnˌtɜːpɹəˈteɪʃən/, evaluation /ɪˌvæljuˈeɪʃn̩/, ratio /ˈɹeɪ.ʃoʊ/, threshold /ˈθɹɛʃ(h)oʊld/
Длинные слова — следите за ударением: classification /ˌklæsɪfɪˈkeɪʃən/, sensitivity /ˌsɛn.səˈtɪv.ə.ti/, interpretation /ɪnˌtɜːpɹəˈteɪʃən/, inheritance /ɪnˈhɛɹɪtəns/, significance /sɪɡˈnɪfɪkəns/

Звуки, трудные для русскоязычных:

/w/ — губы округлены, это не /v/: sequence /ˈsiː.kwəns/, frequency /ˈfɹiːkwənsi/, workshop /ˈwɝk.ʃɑp/, query /ˈkwɪɹ.i/, webinar /ˈwɛb.əˌnɑː/
/h/ — лёгкий выдох, а не русское «х»: inheritance /ɪnˈhɛɹɪtəns/, inherit /ɪnˈhɛɹɪt/, threshold /ˈθɹɛʃ(h)oʊld/, highlight /ˈhaɪˌlaɪt/, likelihood /ˈlaɪklihʊd/
Звонкие согласные в конце слова — не оглушайте их: dosage /ˈdəʊsɪd͡ʒ/, involve /ɪnˈvɑlv/, correspond /ˌkoɹəˈspɑnd/, observe /əbˈzɜːv/, sensitive /ˈsɛn.sɪt.ɪv/

Как заниматься с этим видео

Прослушайте всё видео один раз молча и выпишите незнакомые слова.
Повторяйте предложение за предложением на обычной скорости, пока ваш ритм не совпадёт с ритмом говорящего.
Запишите себя и сравните с оригиналом, обращая внимание на такие слова, как gene, dosage, classification.

Что такое техника Shadowing?

Shadowing — это научно обоснованная техника изучения языка, изначально разработанная для подготовки профессиональных переводчиков и популяризированная полиглотом доктором Александром Аргуэльесом. Метод прост, но эффективен: вы слушаете аудио на английском от носителей языка и немедленно повторяете вслух — как тень, следующая за говорящим с задержкой в 1–2 секунды. В отличие от пассивного прослушивания или грамматических упражнений, Shadowing заставляет мозг и мышцы рта одновременно обрабатывать и воспроизводить реальные речевые паттерны. Исследования показывают, что это значительно улучшает точность произношения, интонацию, ритм, связную речь, понимание на слух и беглость речи — что делает его одним из самых эффективных методов для подготовки к IELTS Speaking и реального общения на английском.

Техника шедоуинга: читать полное пошаговое руководство →

Практика Shadowing: Presentation - Copy Number Variant Interpretation/Dosage Sensitivity Curation (Erica Andersen) - Изучайте разговорный английский по видео

Выберите режим практики

Скачать приложение

Тот же канал

Sequence Variant Literature Search Tips and Tricks

Рекомендуемое видео

CNV analysis with Daniel Howrigan

Presentation of the EDQM activities in the field of Reference Substances

Clinical Cuts - Chronic obstructive pulmonary disease (COPD)

2026 ESC Guidelines for the Management of Cardiovascular Disease and Chronic Kidney Disease

Claude Code Is Wasting Tokens... Microsoft Built a Fix

How We Incorporate Patient Priorities Care into Our Clinical Pharmacy Practices

Cambridge 10 Test 4 Section 4 Listening

Scoliosis: How to medically classify scoliosis (the Lenke System for AIS)

Evaluation of Obesity Studies | Dr. Wendy Bennett

Understanding Cervical Ectropion / Cervical Erosion

Other Corneal Disorders - CRASH! Medical Review Series