Rare Disease 2 —
Training activity: 10

Details

Review referrals; analyse, interpret and report genome-wide copy number assays from WGS and/or microarray testing for patients with chromosomal disorders.

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 for genome-wide copy number assays, specifically distinguishing between those requiring microarray versus Whole Genome Sequencing (WGS)?
• What constitutes a thorough and successful characterisation of copy number variants (CNVs) and other structural variants (e.g., inversions or translocations), ensuring you accurately determine their size, gene content, and genomic orientation?
• How will you demonstrate proficiency in using bioinformatic tools and best practice guidelines (e.g., ACGS or ClinGen) to investigate the clinical significance of identified chromosomal abnormalities?
• What are the standards for a high-quality interpretive report that translates complex cytogenomic findings into clear management recommendations for the patient and their family?
• What specific steps have you planned to gain clarity on the expected depth of analysis for non-standard structural variants?

What is your prior experience of this activity?

• Think about what you already know regarding the technical principles of microarray (aCGH/SNP) and WGS-based copy number calling, and how your previous experience with targeted assays provides a foundation for this genome-wide task.
• Consider possible challenges you might face, such as interpreting small CNVs, variants in regions of variable penetrance, mosaic findings, or resolving discrepancies between different technical platforms (e.g., QF-PCR vs. microarray).
• How do you recognise the scope of your own practice for this activity? In what situations—such as encountering a complex cryptic rearrangement or a novel balanced translocation—will you need to seek immediate advice from a senior Clinical Scientist or Clinical Geneticist?
• How are you feeling about embarking on the analysis of chromosomal disorders, given the significant impact these results have on the diagnostic and management pathway for rare disease patients?

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 bioinformatic tools to delineate precise breakpoints for structural variants or mastering the use of CNV-specific databases like DECIPHER?
• Identify the specific insights you hope to gain regarding genotype-phenotype correlations in chromosomal disorders and how the identification of a structural variant influences recurrence risk and future family testing.
• In what ways do you anticipate this experience will improve your ability to communicate complex genomic findings, particularly in explaining the limitations of different cytogenetic techniques to multidisciplinary colleagues?

What additional considerations do you need to make?

• How will you consult actions identified following previous experiences of variant interpretation or report writing to ensure your approach to CNV analysis is building upon earlier feedback?
• Which specific clinical and technical resources—including National Genomic Test Directory clinical indications, ISCN nomenclature for describing structural variants, and local SOPs for reporting chromosomal abnormalities—have you reviewed to ensure your approach to genome-wide copy number analysis is evidence-based and safe?
• What steps have you planned to ensure your clarity on the local requirements for validating a WGS-detected structural variant using an alternative technology (e.g., FISH)?

In action

During the activity, did anything unexpected occur?

• What surprises or deviations from your plan are you noticing while characterising complex structural variants beyond simple deletions or duplications in genome-wide data?
• How are you managing complex rearrangements (e.g., inversions, translocations, or ring chromosomes) that were not immediately apparent from the initial copy number call?
• In what ways are you resolving data quality issues—such as noisy log R ratios or ambiguous BAF plots—to delineate precise breakpoints?
• How are you addressing discordance between your findings and the reported phenotype, or between results from different technologies like WGS and microarrays?
• How are you evaluating CNVs in regions of variable penetrance or known disorder loci that present with atypical clinical features?

How are you reacting to the unexpected development?

• How is the unexpected finding leading you to adjust your analysis strategy or re-verify phenotypic data in the moment?
• How are you using raw alignment data or sequencing reads to distinguish true structural changes from technical noise?
• Which specialised databases (e.g., DECIPHER, ClinGen) or literature sources are you consulting to investigate novel rearrangements?
• How are you identifying the point where you must seek immediate senior advice to determine if reflex testing, such as FISH or parental studies, is required?
• How are you feeling in that moment, and is the technical complexity or the use of ISCN nomenclature affecting your confidence in reaching a diagnostic conclusion?

What was the conclusion or outcome?

• How effectively are you working within your professional scope of practice, and when do you determine that senior intervention is necessary?
• What insights are you gaining regarding identifying subtle mosaicism or mastering new techniques for delineating breakpoints using WGS?
• In what ways are your real-time decisions ensuring that the final interpretation is safe, high-quality, and provides necessary clarity for clinical management?

On action

What happened?

• How would you summarise the key points of the experience, specifically the types of chromosomal referrals triaged and the range of copy number variants (CNVs) or structural variants (e.g., inversions, translocations) identified?
• What specific events, actions, or interactions felt most important, such as determining the size, gene content, and genomic orientation of a complex rearrangement?
• Which ‘reflect-in-action’ moments did you notice where you had to adapt—for example, by pausing to re-verify raw alignment data or B-allele frequency plots when encountering a potential mosaic finding or technical artifact?
• How did you feel during the experience, particularly when handling the professional responsibility of interpreting high-stakes results for patients with chromosomal disorders?

How has this experience contributed to your developing practice?

• What specific knowledge or skills did you develop regarding the assessment of variant pathogenicity using bioinformatic tools and best practice guidelines (e.g., ACGS or ClinGen)?
• How did this activity improve your proficiency in performing whole genome and chromosomal analysis to accurately characterise complex structural rearrangements?
• What strengths did you demonstrate (e.g., a systematic approach to CNV analysis) and what knowledge gaps were evident (e.g., difficulty applying ISCN nomenclature to a multi-break rearrangement)?
• How does this activity compare against your previous experiences with targeted dosage assays or earlier microarray rotations—were any previously identified actions for development achieved?
• Identify any challenges you experienced, such as resolving discrepancies between technical platforms (e.g., QF-PCR vs. WGS) or managing a Variant of Uncertain Significance (VUS) with limited phenotypic correlation.
• Did you need to seek advice or escalate a case to a senior Clinical Scientist or Clinical Geneticist to ensure you were working strictly within your professional scope of practice?
• How does accurately diagnosing the underlying cause of a chromosomal disorder relate to the requirements for your future post-programme practice as a Clinical Scientist?

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 genotype-phenotype correlations in specialised databases like DECIPHER?
• What will you do differently next time you analyse a genome-wide copy number assay? Has anything changed in how you would justify the selection of a specific reflex test (e.g., FISH or parental studies)?
• Do you need to practise any aspect of the activity further, such as refining your technical troubleshooting of noisy data or mastering the description of complex structural variants?
• What support or resources (e.g., expert mentorship from a bioinformatician, attendance at a cytogenomics workshop, or access to updated international nomenclature manuals) have you identified as necessary for your ongoing development?

Beyond action

Have you revisited the experiences?

• How have you reviewed your actions from previous reflections for this activity to determine if you have completed identified tasks, such as mastering ISCN nomenclature for multi-break rearrangements or refining your use of CNV-specific databases like DECIPHER?
• How has your perspective on interpreting chromosomal rearrangements (e.g., inversions, translocations) evolved as you have encountered a broader range of clinical phenotypes since your initial training cases?
• Comparing these experiences with your Observed Training Activities (OTAs), what specific specialist behaviours—such as the systematic assessment of B-allele frequency plots or the justification of reflex tests—have you assimilated into your routine practice?
• When performing a module review across Paediatric and Prenatal genomics, what overarching patterns or themes have you identified regarding your ability to integrate results from multiple technologies like QF-PCR, microarrays, and WGS?
• In what ways has engaging in discussions with clinical geneticists and senior colleagues shifted your perspective on the complex genotype-phenotype correlations you encountered?

How have these experiences impacted upon current practice?

• How has the accumulated learning from performing genome-wide copy number analysis supported your preparation for observed ‘in-person’ assessments, such as Case-based Discussions (CBDs) regarding the clinical implications of structural variants or a DOPS titled ‘Classify a variant’?
• How has your practice in filtering and prioritising structural variants developed and evolved over time, and can you identify instances where you are now more efficient at distinguishing pathogenic changes from benign background?
• In what ways are you now more confident in recognising the limits of your own professional scope of practice when encountering novel or cryptic rearrangements that require senior specialist review?
• How have the transferable skills in diagnostic planning and clinical reasoning developed here informed your approach to other genomic datasets, such as searching for structural variants in Whole Genome Sequencing (WGS) data?
• How has your appreciation for the ethical and legal dimensions of chromosomal findings shaped the patient-centred approach you take when reporting results that have significant implications for a family’s recurrence risk?
• How will your current mastery of these assays help you contribute to future service improvements or innovations, such as the implementation of new bioinformatic tools for automated structural variant calling?

Relevant learning outcomes

#	Outcome
# 1	Outcome Review referrals for patients referred for rare disease genomic testing.
# 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.