Rare Disease 2 —
Training activity: 14

Details

Analyse, interpret and report repeat expansions detected by WGS.

Type

Entrustable training activity (ETA)

Evidence requirements

Evidence the activity has been undertaken by the trainee repeatedly, consistently, and effectively over time, in a range of situations. This may include occasions where the trainee has not successfully achieved the outcome of the activity themselves. For example, because it was not appropriate to undertake the task in the circumstances or the trainees recognised their own limitations and sought help or advice to ensure the activity reached an appropriate conclusion. ​

Reflection at multiple timepoints on the trainee learning journey for this activity.

Reflective practice guidance

The guidance below is provided to support reflection at different time points, providing you with questions to aid you to reflect for this training activity. They are provided for guidance and should not be considered as a mandatory checklist. Trainees should not be expected to provide answers to each of the guidance questions listed.

Before action

What does success look like?

• How will you identify what is expected of you in relation to triaging referrals where a repeat expansion is the primary differential or an unexpected WGS finding?
• What constitutes a thorough and successful analysis of WGS data for repeat expansions, ensuring you accurately identify repeat sizes and use appropriate bioinformatic tools to determine their significance?
• How will you demonstrate that your interpretive reports meet the distinct standards required for diagnostic, presymptomatic, or carrier testing, ensuring management recommendations are clear and safe?
• In what ways do you plan to use this activity to practice demonstrating appropriate communication skills, particularly in explaining the technical limitations of WGS for sizing large expansions to clinical colleagues?
• What steps have you planned to gain clarity on the required depth of analysis and local reporting templates for repeat expansions?

What is your prior experience of this activity?

• Think about what you already know regarding the genetic mechanisms of repeat expansion disorders (e.g., Huntington’s, Myotonic Dystrophy, or Fragile X) and your experience with traditional PCR-based fragment analysis.
• Consider possible challenges you might face, such as distinguishing between true expansions and technical sequencing artifacts, or managing the sizing uncertainty inherent in short-read WGS data.
• How do you recognise the scope of your own practice? In what situations—such as encountering a borderline result near a clinical threshold or a repeat in a novel locus—will you need to seek immediate advice from a senior Clinical Scientist or bioinformatician?
• How are you feeling about embarking on the analysis of high-stakes results, given that repeat expansions often have significant life-altering implications for healthy individuals and their relatives?

What do you anticipate you will learn from the experience?

• What specific analytical skills do you want to develop, such as refining your ability to use and interpret the output of specialised bioinformatic tools for repeat detection in whole genome data?
• Identify the specific insights you hope to gain regarding the clinical utility of WGS in identifying pathogenic expansions that may have been missed by targeted testing or that present with atypical phenotypes.
• In what ways do you anticipate this experience will improve your ability to translate complex technical data into clear, sensitive, and actionable reports for non-genomics specialists?

What additional considerations do you need to make?

• How will you consult actions identified following previous experiences of variant interpretation or WGS analysis to ensure your approach to repeat expansion detection is building upon earlier feedback?
• Which specific resources and clinical standards—including National Genomic Test Directory eligibility, pathogenic repeat ranges, and local SOPs for orthologous validation—have you reviewed to ensure your approach to analysing WGS-detected repeat expansions is evidence-based and safe?
• What steps have you planned to ensure your clarity on the limits of your responsibility when resolving complex interpretative issues in the WGS repeat expansion workflow?

In action

During the activity did anything unexpected occur?

• Are you noticing anything surprising or different from what you anticipated while navigating the WGS alignment data, such as an atypical read distribution that suggest a repeat expansion larger than the initial bioinformatic estimate?
• How are you addressing identified repeat expansions that contradict the clinical phenotype or reported family history?
• In what ways are you managing data quality issues, such as noise or low coverage at critical regions (e.g. HTT, DMPK, FMR1), to accurately delineate expansion sizes?
• How are you navigating borderline results near clinical thresholds where the distinction between alleles remains unclear in the WGS data?
• How does this live experience with WGS-detected expansions compare to your prior experiences with PCR-based fragment analysis for similar triplet repeat disorders?

How are you reacting to the unexpected development?

• How is the finding impacting your actions in the moment? For example, are you adjusting your filtering parameters or pausing to re-verify the phenotypic data against the specific gene locus?
• How are you reviewing raw sequencing reads or using visualisers to distinguish a true expansion from a bioinformatic artifact?
• What evidence are you gathering from specialised tools (e.g. ExpansionHunter) or recent literature to clarify a novel or borderline repeat finding?
• How are you identifying when to seek senior advice regarding the necessity of urgent orthologous validation (e.g. TP-PCR) before reporting?How are you feeling in that moment? Is the technical uncertainty or the potential for a life-altering diagnosis affecting your confidence in reaching a successful diagnostic conclusion?

What was the conclusion or outcome?

• How effectively are you working within your professional scope of practice? Are you successfully managing the interpretation of the expansion yourself, or have you identified the point where senior intervention is necessary to ensure patient safety?
• What are you learning as a result of these unexpected developments? For instance, are you mastering a new troubleshooting technique for sizing repeats in short-read data or gaining insight into the clinical relevance of specific alleles in adult-onset disorders?
• In what ways are your real-time decisions ensuring that the final interpretation is safe, high-quality, and provides the necessary clarity to inform the clinical management of the patient and their family?

On action

What happened?

• How would you summarise the key points of the WGS repeat expansion cases you handled, specifically regarding the types of disorders and the range of alleles identified?
• What specific events, actions, or interactions—such as navigating “anchoring reads” or managing a borderline result—felt most significant during the analysis?
• Which ‘reflect-in-action’ moments did you notice where you had to adapt, for instance, by re-verifying phenotypic data when a finding contradicted the family history?
• How did you feel during the experience, particularly when handling the professional responsibility of interpreting results with life-altering implications?

How has this experience contributed to your developing practice?

• What specific knowledge or skills did you develop regarding the assessment of clinical significance for repeats detected by whole genome analysis?
• What strengths did you demonstrate (e.g., systematic use of bioinformatic tools) and what knowledge gaps were evident (e.g., uncertainty regarding the technical limitations of short-read data for large expansions)?
• How does this WGS experience compare against your previous practice using PCR-based fragment analysis—were any previously identified actions for development achieved?
• In what ways did you successfully manage interpretative challenges, such as resolving discrepancies between bioinformatic estimates and clinical presentations?
• How did you ensure you were working within your scope of practice, and can you identify a point where you escalated a case to a senior Clinical Scientist or bioinformatician?
• How does the proficiency you gained in communicating these complex findings relate to the requirements for your future post-programme practice?

What will you take from the experience moving forward?

• What specific actions will you now take to support the assimilation of what you have learned, such as reviewing national guidelines for normal and pathogenic repeat ranges?
• What will you do differently next time you encounter a borderline result in WGS data?
• Has anything changed in how you would justify the need for orthologous validation (e.g., TP-PCR) to clinical colleagues?
• Do you need to practise any aspect of the activity further, such as refining your technical troubleshooting of noisy data at critical repeat loci?
• What support or resources (e.g., specialist neurogenetics databases or mentorship from a bioinformatician) have you identified as necessary for your ongoing development?

Beyond action

Have you revisited the experiences?

• How have you evaluated and re-evaluated your initial analytical strategies for detecting repeat expansions in WGS data (e.g. using ExpansionHunter) in light of subsequent cases or technical updates?
• Have you reviewed your actions from previous reflections for this activity to determine if you have completed identified tasks, such as mastering the interpretation of intermediate alleles or refining your use of local SOPs for orthologous validation?
• When performing a module review across your rare disease activities, what overarching patterns or learning themes have you identified regarding your ability to manage the technical limitations of short-read WGS for sizing large expansions?
• In what ways has discussing with senior clinical scientists or bioinformaticians regarding borderline results led to a transformation in your approach to assessing clinical significance?
• Are you now ready to demonstrate this new learning in practice when navigating the technical and ethical complexities of high-stakes presymptomatic results?

How have these experiences impacted upon current practice?

• How has the accumulated learning from interpreting complex WGS repeat data supported your preparation for observed ‘in-person’ assessments, such as a Case-based Discussion (CBD) on neurogenetic pathways or a DOPS titled ‘Classify a variant’?
• How has your practice in correlating repeat size with clinical phenotype developed and evolved over time, and can you identify instances where you are now more efficient at distinguishing technical artifacts from true expansions?
• In what ways are you now more confident in recognising the limits of your own professional scope of practice when encountering novel repeat loci or results near clinical thresholds that require senior specialist review?
• How has your foundational knowledge of repeat expansion mechanisms (e.g. anticipation or somatic mosaicism) informed your problem-solving in other genomic areas, such as interpreting complex family histories?
• How effectively are you now able to use bioinformatic tools and best practice guidelines to investigate the clinical significance of variants compared to your initial attempts during this training activity?

Relevant learning outcomes

#	Outcome
# 2	Outcome Analyse, interpret and report results for diagnostic, presymptomatic and familial/carrier rare disease genomic testing.
# 3	Outcome Perform targeted analysis, whole genome analysis, and chromosomal analysis for patients referred for rare disease genomic testing.
# 4	Outcome Interpret genomic variants to investigate their clinical significance for patients referred for rare disease genomic testing.
# 7	Outcome Employ specialist knowledge of rare disease genomic testing to deliver a safe and high-quality service.
# 8	Outcome Demonstrate appropriate communication skills with healthcare professional colleagues to inform the clinical management of patients referred for rare disease genomic testing.