Best Practices for Clinical Whole Genome Sequencing
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Questions and Answers

What should genotype-driven analyses aim to capture regarding variants?

Genotype-driven analyses should aim to capture all variants that may be classified as pathogenic or likely pathogenic.

What types of variants are prioritized during the analysis of multiple family members?

Variants suspected based on their inheritance pattern, such as de novo variants or biallelic rare variants, are prioritized.

Why are clinical laboratories encouraged to include analysis of genes not yet linked to disease?

Including such analysis may help in discovering novel disease genes and aid in understanding genotype-phenotype correlations.

What challenges exist in the automated prioritization of pathogenic variants?

<p>Automated prioritization can be challenging due to the unstructured nature of the scientific literature.</p> Signup and view all the answers

How can software tools assist analysts in identifying variants with disease associations?

<p>Software tools can identify variants previously reported in association with any phenotype using literature searches or database entries.</p> Signup and view all the answers

What role does the ClinVar database play in genotype-phenotype analysis?

<p>ClinVar serves as a critical database for reporting variants associated with phenotypes.</p> Signup and view all the answers

What types of variants are highlighted in automated prioritization based on gnomAD constraint scores?

<p>Automated prioritization focuses on de novo and pLOF variants in highly constrained genes.</p> Signup and view all the answers

How should genotype-driven analysis be supplemented for comprehensive results?

<p>Genotype-driven analysis should be supplemented with additional phenotype-driven analyses.</p> Signup and view all the answers

What is the importance of phenotype-driven and genotype-driven filtering strategies in reviewing single nucleotide variants?

<p>These strategies are crucial for identifying unanticipated genetic diagnoses that may explain patient phenotypes.</p> Signup and view all the answers

What are the potential outcomes from applying an unbiased analysis approach to variant detection?

<p>Outcomes include discovering unexpected genetic diagnoses and understanding rare presentations of established disorders.</p> Signup and view all the answers

Why is it important to consider all possible consequences of single nucleotide variants?

<p>Considering all consequences, like splicing annotations and transcript-specific impacts, is vital for accurate interpretation of variant effects.</p> Signup and view all the answers

What types of genetic diagnoses can be revealed through the analysis of single nucleotide variants?

<p>Multiple genetic diagnoses, variants relevant to secondary phenotypes, and those linked to family history of disease can be revealed.</p> Signup and view all the answers

What role do resources like ClinGen play in the identification of high-frequency variants?

<p>ClinGen assembles resources that aid in identifying pathogenic high-frequency variants to ensure they are thoroughly reviewed.</p> Signup and view all the answers

What is meant by phenotypic expansion in the context of variant analysis?

<p>Phenotypic expansion refers to identifying patients with unusual presentations of established disorders mediated by genetic variants.</p> Signup and view all the answers

What are the implications of finding clinically significant incidental or secondary findings?

<p>Clinically significant findings can inform patient management and preventative strategies for conditions not initially suspected.</p> Signup and view all the answers

What challenges are associated with multi-allelic variants in single nucleotide variant analysis?

<p>Multi-allelic variants present challenges in determining the significance of each allele's contribution to the patient's phenotype.</p> Signup and view all the answers

What is the primary advantage of whole genome sequencing (WGS) compared to other sequencing methods?

<p>WGS allows detection of a broad range of variant types in a single assay, making it more comprehensive.</p> Signup and view all the answers

What types of genetic variants can be detected by whole genome sequencing?

<p>WGS can detect single nucleotide variants (SNV), small insertions and deletions, mitochondrial variants, repeat expansions, copy number variants, and structural variants.</p> Signup and view all the answers

How does WGS ensure uniform coverage of genomic regions?

<p>WGS is untargeted, resulting in more uniform coverage of exonic regions and added coverage of intronic, intergenic, and regulatory regions.</p> Signup and view all the answers

What was the purpose of the Medical Genome Initiative's working group?

<p>The working group aimed to establish best practice recommendations for the interpretation and reporting of clinical diagnostic WGS.</p> Signup and view all the answers

What discrepancy was noted between whole exome sequencing (WES) and whole genome sequencing (WGS) in the recent meta-analysis?

<p>The meta-analysis found no significant difference in yields between WES and WGS.</p> Signup and view all the answers

What methods were used to guide the discussions and development of the best practice recommendations?

<p>Informal polling during teleconference meetings was used to gather insights from participating laboratories.</p> Signup and view all the answers

What should newly issued test requisition forms indicate regarding genetic variants?

<p>They should indicate that genetic variants relevant to newly published variant or gene-level evidence may allow a previously unreviewed variant to meet criteria for expert review.</p> Signup and view all the answers

What are some of the key areas that lack consensus in the adoption of WGS?

<p>Areas lacking consensus include requisition/consent, data annotation, analysis, triage, variant curation, reporting, and reanalysis.</p> Signup and view all the answers

How might laboratories suggest a time period for reanalysis of genetic tests?

<p>Laboratories may suggest a minimum time period, such as one year, to have elapsed since the initial analysis before conducting a reanalysis.</p> Signup and view all the answers

Why might comparisons between cohorts in genetic sequencing be limited in utility?

<p>Comparisons may be limited due to variability introduced by factors such as patient age groups, clinical indications, and family structures.</p> Signup and view all the answers

What triggers reactive reanalysis in a laboratory setting?

<p>Reactive reanalysis is triggered when a request is made by the ordering provider or patient.</p> Signup and view all the answers

In what way can reanalysis be initiated proactively?

<p>Proactive reanalysis can be initiated by new publications, updated transcripts, new gene models, or changes in the WGS test definition.</p> Signup and view all the answers

What is the importance of clarifying phenotypic data before testing?

<p>Clarifying phenotypic data ensures that laboratory staff can accurately assess and interpret the relevance of the information prior to initiating testing.</p> Signup and view all the answers

What is the role of policies regarding secondary findings in genetic testing?

<p>Policies for secondary findings analysis should be developed in advance to define how incidental findings will be reported and managed.</p> Signup and view all the answers

What should requisition and consent forms clarify for trio or multiple-family member sequencing?

<p>They should clarify how the data from auxiliary family members will be used and reported.</p> Signup and view all the answers

Why is proactive reanalysis recognized as an important step in WGS testing?

<p>Proactive reanalysis is recognized as important because it maximizes the clinical utility of WGS tests through updates from new clinical information.</p> Signup and view all the answers

What is the recommended process for reviewing monoallelic variants in autosomal recessive genes?

<p>A compelling monoallelic variant in an autosomal recessive gene should be re-examined by at least two trained staff members.</p> Signup and view all the answers

Why is it important for automated analysis tools to be assessed by human analysts?

<p>The sensitivity and specificity of automated analysis tools are insufficient, necessitating careful review by human analysts before reporting.</p> Signup and view all the answers

What should be included in laboratory policies regarding findings considered for return?

<p>Policies should define the types of findings to return and ensure they are available to both patients and providers.</p> Signup and view all the answers

What tools are recommended for systematic proactive reanalysis of variants?

<p>Tools that automatically identify new scientific literature relevant to previously reviewed variants and genes are recommended.</p> Signup and view all the answers

How should results from automated analyses be handled before reporting?

<p>Results from automated analyses should be carefully assessed by a human analyst prior to consideration for reporting.</p> Signup and view all the answers

What is the goal of the laboratory's reporting policies?

<p>The goal is to maximize the diagnostic potential of tests while minimizing the number of variants of uncertain significance reported.</p> Signup and view all the answers

What type of evidence should be addressed when returning variant findings?

<p>Variant-level evidence, gene-level evidence, and the correlation between the patient’s phenotype and the gene should be addressed.</p> Signup and view all the answers

Why is open communication encouraged between ordering providers and the laboratory?

<p>Open communication is encouraged, especially for challenging cases, to clarify uncertainties regarding how findings align with patient phenotypes.</p> Signup and view all the answers

What is the primary role of automated phenotyping in clinical genome sequencing?

<p>Automated phenotyping assists in identifying genetic diseases by analyzing electronic health records to match clinical features with genotypes.</p> Signup and view all the answers

What are copy-number variants and why are they significant in genetic disorders?

<p>Copy-number variants (CNVs) are alterations in the number of copies of a particular gene or region of the genome, significant for their role in various genetic disorders including developmental delays and congenital anomalies.</p> Signup and view all the answers

How does Face2Gene facilitate the identification of genetic syndromes?

<p>Face2Gene uses facial recognition technology to analyze facial features and identify potential congenital dysmorphic syndromes based on visual phenotypes.</p> Signup and view all the answers

What is the significance of structural variation reference in medical genetics?

<p>A structural variation reference is crucial for understanding genetic diversity and the impact of different structural variants on health in both medical and population genomics.</p> Signup and view all the answers

What are the main challenges in detecting long-read assemblies from short-read genome sequencing technologies?

<p>Challenges include accurately identifying complex structural variants and resolving repetitive regions in the genome that short reads struggle to represent.</p> Signup and view all the answers

Why is the Human Disease Ontology significant in genetic research?

<p>The Human Disease Ontology provides a standardized framework for classifying and organizing disease-related information, facilitating better communication and data sharing in genetic research.</p> Signup and view all the answers

Describe the ethical considerations involved in handling incidental findings in genetic testing.

<p>Ethical considerations include the obligation to inform patients about incidental findings that could have health implications, and the need to balance this with the patient’s right not to know.</p> Signup and view all the answers

What role do guidelines such as those from ACMG/AMP play in mitochondrial DNA variant interpretation?

<p>ACMG/AMP guidelines provide a standardized approach for evaluating the clinical significance of mitochondrial DNA variants, ensuring consistency in genetic counseling and diagnosis.</p> Signup and view all the answers

Study Notes

Best Practices for Clinical Whole Genome Sequencing

  • Whole genome sequencing (WGS) is emerging as a first-tier diagnostic test for rare genetic disorders, offering a more comprehensive approach than whole exome sequencing or other targeted sequencing assays.
  • WGS is superior because it can detect a broader range of variant types like single nucleotide variants (SNVs), insertions/deletions, mitochondrial variants, repeat expansions, copy number variants (CNVs) and other structural variants (SVs) within a single assay. It also provides more uniform coverage of exonic regions and intronic, intergenic, and regulatory regions.
  • The Medical Genome Initiative (MGI) developed best practice recommendations for WGS interpretation and reporting, focusing on the interpretation and reporting of clinical diagnostic WGS.

Clinical Diagnostic Genomic Sequencing Phases

  • Analysis is divided into three phases:
    • Primary analysis: technical components of the assay like DNA extraction, library preparation, sequence generation, and preliminary data quality control (QC)
    • Secondary analysis: bioinformatic processes such as aligning raw sequence data to a genome reference, variant calling, and other similar processes
    • Tertiary analysis: includes annotation, filtering, prioritization, classification of variants, case interpretation, and reporting.

Interpretation and Reporting Considerations for Clinically Relevant Variants

  • Single Nucleotide Variants (SNVs): require phenotype-driven and genotype-driven filtering, considering splicing, transcript-specific impacts, and multi-nucleotide variants (MNVs).
  • Small Insertions/Deletions (indels): Validation and orthogonal confirmation might be needed for accuracy, prioritizing quality, frequency, and overlap with protein-coding regions.
  • Copy Number Variation (CNV): Filtering based on quality, frequency, and overlap with protein-coding regions, and using inheritance and copy number review during triaging. Review of the depth-based plot and B-allele frequency plot across the genome to identify large CNVs is crucial.
  • Balanced and Complex Structural Variants (SV): Primarily used for identifying recurrent pathogenic balanced structural variants, refining CNVs, directed SV searches in known regions, and investigating runs of homozygosity (ROH).
  • Runs of Homozygosity (ROH): Extensive ROH on a chromosome can indicate uniparental disomy (UPD), while ROH across chromosomes may be due to consanguinity.
  • Repeat Expansions: Emphasizes orthogonal testing for repeat length confirmation and visual alignment inspection to confirm allele expansions and identify interruptions.
  • Mitochondrial Variants: Focuses on heteroplasmy, heteroplasmy thresholds for disease manifestation, variable inter- and intra-familial phenotype expressivity, and sample origin variations.
  • Mosaic Variants: Lower WGS coverage compared to WES or panel testing, indicating a need for orthogonal testing.
  • Polygenic Risk Scores (PRS): Should specify ancestry for calculations and acknowledge any limitations based on ancestry in interpretation.

Reanalysis

  • Periodic case reanalysis is recommended to improve the diagnostic yield.
  • Reanalysis policies should be established in advance and communicate to providers during test ordering.

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Best Practices for Clinical Whole Genome Sequencing (PDF)

Description

Explore the best practices for whole genome sequencing (WGS) as a diagnostic tool for genetic disorders. This quiz will cover its advantages over whole exome sequencing, and delve into the phases of clinical genomic sequencing and interpretation. Understand the comprehensive approach that WGS offers in detecting various genetic variants.

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