Causal Variant Identification Strategies

Questions and Answers

What is a key advantage of the gnomAD database over the ExAC database?

It provides a broader range of functional variant information. (correct)

It features only pathogenic variants.

It contains variants in non-coding regions.

It includes larger sample sizes for rare diseases.

Which criterion is least effective for identifying candidate causal genetic variants?

Variants affecting splicing and regulatory elements.

Variants that are typically conserved across species.

Variants linked to common diseases. (correct)

Variants identified as pathogenic.

Which factor restricts the use of WGS in clinical care?

Availability of sequencing technologies.

Limited understanding of variant effects. (correct)

Cost of whole genome sequencing.

The total number of variants analyzed.

In what scenario is WGS most likely to be used effectively?

For individuals with established monogenic diseases. Signup and view all the answers

What is one limitation of reporting from whole genome sequencing?

Restricted only to variants in protein coding sequences. Signup and view all the answers

Which type of research typically utilizes sequences from groups of affected individuals?

Rare disease discovery science. Signup and view all the answers

In the context of rare disease diagnostics, what is often sequenced?

The affected individual and immediately related family members. Signup and view all the answers

Which type of variant is less likely to be beneficial when attempting to make a clinical diagnosis using WGS?

Variants associated with complex diseases. Signup and view all the answers

What is the main purpose of the National Participant Panel in the 100,000 Genomes Project?

To ensure participant interests are prioritized Signup and view all the answers

What constitutes a Tier 1 variant in the standardization of reported variants?

Clear loss of function variants known to be pathogenic Signup and view all the answers

How does Genomics England enable collaboration among gene interpretation stakeholders?

By supplying web-based tools for data analysis Signup and view all the answers

What is the role of the GeCIP Board in relation to participant data?

To oversee who should have access to participant data Signup and view all the answers

What kind of variants are classified as Tier 2 in the reporting system?

Missense variants and other variants of uncertain significance Signup and view all the answers

Which statement best describes the purpose of establishing a 'green list' gene panel?

To classify genetic variants for improved clinical interpretation Signup and view all the answers

What type of condition information is considered optional in patient data collection?

Carrier status for parents of children with rare diseases Signup and view all the answers

What is the intended outcome of engaging the scientific community in the genomics project?

To encourage open debate and establish consensus on genetic panels Signup and view all the answers

What is the likely benefit of diagnosing a mutation in the GLUT1 gene in a child with epileptic encephalopathy type 9?

It confirms the genetic origin of a previously unexplained condition. Signup and view all the answers

What significant information can be inferred from the mutation found in the CTSP1 gene for the girl with life-threatening chicken pox?

It leads to a planned curative bone marrow transplant. Signup and view all the answers

What is the main purpose of PanelApp as described in the content?

To standardize gene-disease related information. Signup and view all the answers

Which statement best reflects the challenges faced by the girl in the case of the GLUT1 mutation?

She underwent a long diagnostic odyssey before the mutation was found. Signup and view all the answers

Why was the mutation in the CTSP1 gene not previously recognized by immunologists?

There had been no prior cases reported with chicken pox correlation. Signup and view all the answers

In the context of gene panels on PanelApp, what does 'de novo' mutation imply?

The mutation occurred for the first time in the affected individual. Signup and view all the answers

What aspect does the PanelApp Gene Panel View primarily focus on?

Facilitation of user comments and reviews of gene panels. Signup and view all the answers

What can be concluded about the risk of recurrence in another child for the family of the girl diagnosed with GLUT1 mutation?

It is very low based on genetic evidence. Signup and view all the answers

What is the primary purpose of using gnomAD in the identification of causal variants?

To identify variants that are frequently observed across populations Signup and view all the answers

Which of the following elements is NOT considered when looking for variants that affect functional elements?

Gene expression level Signup and view all the answers

Why might conserved variants be prioritized in the identification of causal variants?

Because conserved variants indicate importance in evolution Signup and view all the answers

What distinguishes gnomAD from ExAC?

gnomAD contains a larger number of genomes and exomes Signup and view all the answers

What type of analysis can be conducted using the functional annotation of the reference genome?

Evaluating variant occurrence between affected and unaffected individuals Signup and view all the answers

Which of the following databases focuses solely on coding regions of variants?

ExAC Signup and view all the answers

Which strategy is emphasized for identifying variants linked to a particular condition?

Identify variants in genes that are well-characterized in literature Signup and view all the answers

What type of data does gnomAD include to assist in variant filtering?

Exomes and whole genomes from diverse populations Signup and view all the answers

What significant mutation was identified in the case of choroideremia?

A causative non-coding mutation upstream of the X chromosome CHM gene Signup and view all the answers

Which of the following cancers is NOT mentioned as part of the common cancers included in the analysis?

Liver cancer Signup and view all the answers

What is the role of the Genomic Medicine Centres in the National Genomic Medicine Service?

To collect samples and analyze genomic data Signup and view all the answers

What proportion of cancer cases, according to the data, potentially contains actionable findings?

50% Signup and view all the answers

Why is it essential to analyze the promoter region of the CHM gene in diagnosing choroideremia?

To allow diagnosis in other families with similar mutations Signup and view all the answers

What element of the National Genomic Medicine Service aids in the ongoing development through clinical care?

Industry partnerships Signup and view all the answers

What significant change is highlighted regarding the handling of tumor samples for genetic testing?

Samples should be frozen for genetic tests Signup and view all the answers

What was the total number of genomes that had been sequenced by the time indicated in the project status?

112,198 Signup and view all the answers

What is the expected number of whole genomes sequenced from the NHS over the next five years?

500,000 Signup and view all the answers

What benefit does the identification of a causative non-coding mutation provide for families?

It enables cascade testing for at-risk relatives Signup and view all the answers

Study Notes

Identifying Causal Variants

gnomAD (Genome Aggregation Database) contains >125,000 exomes and >15,000 whole genomes; serves as an upgrade from ExAC, which focused solely on coding regions.
Consider variants labeled as pathogenic and those found in genes associated with specific conditions.
Analyze variants affecting functional elements such as:
- Protein coding sequences
- Splicing mechanisms
- Regulatory elements
Prioritize variants that are conserved across species, indicating biological importance.

Sources of Variant Information

Functional annotations derived from the annotated reference genome are crucial for analysis.
Evaluate occurrence rates of variants in affected versus unaffected individuals.

Current Gene Annotation

GENCODE 39 offers updated statistics on human gene annotation, contributing to variant identification and interpretation.

Clinical Applications of WGS

Whole genome sequencing (WGS) benefits monogenic disease diagnostics; more complex diseases remain challenging.
Focus on patients with clear phenotypes for effective variant identification.
Reporting mainly addresses protein coding variants due to predictability of their effects.

Patient Involvement in Genomic Projects

The National Participant Panel ensures participant interests are central to the 100,000 Genomes Project.
Panel responsibilities include responding to feedback and overseeing access to participant data.

Genome Interpretation Providers

A pilot phase contracts are in place for up to 8000 genomic reports.
Genomics England is developing web-based tools for collaboration in clinical interpretation of genomic data.

Tiering of Reported Variants

Variants categorized into three tiers based on association with known genes and the type of mutation:
- Tier 1: Known pathogenic, loss-of-function variants within gene panels.
- Tier 2: Missense mutations and variants of uncertain significance (VUS) within gene panels.
- Tier 3: Variants not included in the gene panels.

Aims of Gene Panel Standardization

Develop a green list of diagnostic grade gene panels for precise classification of genetic variants.
Facilitate consensus within the scientific community regarding gene-disease associations and standardization of terminology.

Case Studies Highlighting WGS Utility

Epileptic Encephalopathy Case: Identified a de novo mutation in the GLUT1 gene, resolving a four-year diagnostic journey and opening avenues for tailored therapies.
Persistent Infections Case: A child with severe infections was found to have mutations in the CTSP1 gene, leading to a potential curative bone marrow transplant to address immune deficiencies.
Choroideremia Case: Discovery of a non-coding mutation upstream of the CHM gene allowed for cascade testing in familial cases and standardization of diagnostic methods.

Current Cancer Genome Projects

Initial focus on common cancers (lung, breast, ovarian, prostate) expanded to include rare cancers and pediatric cancers.
Movement towards a complex NHS transformation in molecular pathology, emphasizing the need for dual preservation of tumor samples for different types of testing.

Cancer Whole Genome Analysis Reporting

Preliminary reports categorize variants based on relevance to cancer treatment.
Future applications may involve drug development and targeted treatment selection.

Status of Genomic Projects

As of June 2019, over 122,000 cancer and rare disease samples collected and analyzed, with 20-25% yielding actionable findings for rare diseases and approximately 50% for cancer cases.

National Genomic Medicine Service

Initiated in October 2018, enhancing genetic testing capabilities across the NHS with ongoing updates to the National Test Directory.
Plans to sequence up to 500,000 whole genomes in the next five years, actively engaging in research partnerships.

Acknowledgments

Recognition of contributions from patients, families, various health teams, and institutions involved in genomic medicine and research.

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Description

This quiz covers key strategies for identifying causal variants in genetic studies, focusing on the use of the gnomAD database and comparisons with previous databases like ExAC. It addresses methods for filtering observed variants and highlights the importance of pathogenic variants and functional elements. Test your knowledge on these essential concepts in genetics.