Clinical Interpretation and Application of Genomic Findings in Rare Disease

Details

Title

Clinical Interpretation and Application of Genomic Findings in Rare Disease

Type

Stage Two

Module code

HBI116

Requirement

Compulsory

Module objective

By the end of this module Clinical Scientists in HSST will be able to analyse, synthesise, critically evaluate and apply knowledge of methods for clinical interpretation of genomic findings, including the range of methods used to interpret genetic test results. They will select and apply the appropriate methods to interpret genetic findings, demonstrating the attitudes and behaviours necessary for overcoming the complexities and uncertainties that can surround interpretation of genetics findings. Although CCSs in Bioinformatics are unlikely to have a diagnostic caseload in the same way as a Genetics Clinical Scientist, they will be expected to appreciate the diagnostic workflow and understand the process so they are able to apply their domain expertise in an appropriate manner. They will contribute to the reporting of diagnostic test results, and therefore the diagnosis of patients, through application of their skills and by taking part in activities such as MDT meetings. They will also understand the impact of diagnostic reports on patients, carers, family members and for future clinical management.

Knowledge and understanding

By the end of this module Clinical Scientists in HSST will be able to analyse, synthesise, evaluate and critically apply their expert knowledge to clinical diagnostic interpretation, including:

Patient perspective

• The ethical, legal and social implications of genomic testing on patients and the impact on family members.
• The impact of genomic findings on the patient and patient care.
• How to provide meaningful genomics information.

Genetic diagnosis

Clinical presentation of a range of inherited rare diseases and syndromes

• The purpose of genetic testing in a variety of scenarios.
• The process by which genetic findings are interpreted, both in constitutional and somatic scenarios, including mitochondrial genetics.
• The interpretation of variants for pharmacogenetics.

Challenges associated with genetic diagnosis

• The interpretational challenges associated with complex genetic disorders and risk measurements.
• The limitations of genomic resources, including presence versus absence in a database, ethnicity and uneven sampling.
• The interpretational issues around tissue types and alternative transcripts.

Evidence-based interpretation of findings

• All major genomic databases used for clinical interpretation of genetic findings, including population, disease, locus-specific and general sequence databases.
• The major tools used for automated annotation of genetic findings and limitations of their annotation sources.
• The consequences of applying control population variant frequency thresholds (e.g. 1% Mutation Annotation Format [MAF], 3% MAF, Database of Genomic Variants [DGV]) and demonstrate selection of appropriate thresholds for different clinical situations.
• The utility of functional studies to determine effects of variants.
• RNA (or protein) studies for elucidating splice, non-coding and deep intronic variants, including importance of tissue type and alternative transcripts.
• The availability (or lack) of validated, appropriate functional assays for performing functional studies.
• The application of phase information, the significance of being in cis or trans with another variant, and the utility of segregation analysis for clinical interpretation of variants.
• How phenotype-genotype associations can be derived and how they can be proven.
• How to evaluate relevant software tools/algorithms used for prediction of variant pathogenicity, including those making predictions at nucleotide, protein and functional network levels, predictions of effects on splicing, and conservation.
• The role (including limitations) of predictive tools and previously detected variants in clinical interpretation of genetic findings.
• Using modes of inheritance to help interpret findings.
• Application of linkage and pedigree analysis to interpret findings for Mendelian diseases.
• Calculating risk, including use of Bayesian methods.
• Understand the concept of penetrance and describe examples of the molecular mechanism.
• Describe how prevalence can affect genetic testing for a disease.

Data collection and sharing

• The requirement for, and utility of, maintaining internal databases of findings, their clinical interpretation and resulting genotype-phenotype associations.
• The requirement for and utility of data sharing between clinical laboratories at national and international levels.

Best practice and accreditation

• Reporting guidelines for genetic testing, including how to describe findings, explain interpretation, recommending follow-up testing and testing further family members.
• The role of best practice and standards in clinical diagnostics using the examples of existing national and international guidelines.
• The role of International Standardization Organisation accreditation in this context.
• The role of risk management in the delivery of a safe, high-quality service.

Technical and clinical skills

By the end of this module Clinical Scientists in HSST will have a critical understanding of current evidence and its application to the performance and mastery of a range of technical skills. In addition, they will be able to identify suboptimal areas of practice and recommend improvements, and will:

• Ensure genomics services are delivered in clean and safe environments that are fit for purpose, based on national best practice.
• Use a range of major tools for automated annotation of genetic findings and know the limitations of their annotation sources.
• Use a range of major genomic databases for clinical interpretation of genetic findings, including population, disease, locus-specific and general sequence databases.
• Evaluate relevant software tools/algorithms used for prediction of variant pathogenicity, including those making predictions at nucleotide, protein and functional network levels, predictions of effects on splicing, and conservation.
• Implement and evaluate a variant annotation pipeline that is appropriate to a specific genetic test, including a document describing the design, assumptions and limitations, according to best available practice.
• Compile a comprehensive casebook of variants that details the interpretational workflow that leads to the reported result, including recommendations for and examples of results of follow- up testing and family studies. The casebook should cover a wide range of tests, findings, results and be representative of the spectrum of clinical service.

By the end of this module the Clinical Scientist in HSST will be expected to critically reflect and apply in practice a range of clinical and communication skills with respect to clinical interpretation. They will communicate effectively with the public, patients, carers, clinicians, academics and other healthcare professionals, and will:

• Contribute to the discussion of selected cases at a MDT meeting, including a defence of the bioinformatics approaches to the interpretation of findings.
• Describe in language that is accessible to Clinical Scientists in other specialisms, the clinical consequences of a genetic finding and then summarise and justify the evidence from bioinformatics analyses used to inform that conclusion.
• Describe in language that is accessible to clinicians, the clinical consequences of a genetic finding and then summarise and justify the evidence from bioinformatics analyses used to inform that conclusion.
• Draft 10 full diagnostic reports detailing a genetic finding, provide interpretation, recommend follow-up and further family testing.
• Discuss functional validation of a genetic finding with relevant stakeholders (such as the lab delivering the functional test).
• Critically evaluate analytical results from complex investigations.
• Synthesise very complex information and relay it in a way that can outline the decision-making process to trainees, other staff and the MDT for reflection and training.
• Take responsibility for the legal and practical requirement for accurate and contemporaneous record keeping, ensuring compliance with national standards and provide scientific advice as required.
• Work within professional boundaries and understand the limitations and need to refer appropriately to other members of the MDT.