Rare Disease 2 —
Training activity: 8

Details

Review referrals; analyse, interpret and report the results of Sanger sequencing analysis for cascade testing to include:

• predictive/presymptomatic testing
• carrier testing
• family studies

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 predictive, carrier, and family studies?
• What constitutes a successful interpretation and analysis of Sanger sequencing electropherograms for a known familial variant, ensuring the clinical significance is accurately conveyed?
• How will you demonstrate that your interpretive reports meet the distinct standards required for healthy family members (e.g., predictive vs. carrier status) to ensure a safe and high-quality service?
• In what ways do you plan to use this activity to practice demonstrating appropriate communication skills, particularly in how you phrase management recommendations for different clinical scenarios?
• What steps have you planned to discuss these expectations to gain clarity on the required depth of analysis and local reporting templates?

What is your prior experience of this activity?

• Think about what you already know about Mendelian inheritance and the technical principles of Sanger sequencing analysis.
• Consider possible challenges you might face, such as interpreting poor-quality traces, identifying technical artefacts, or managing the ethical complexities of unexpected results (e.g., non-segregation or non-paternity).
• How do you recognise the scope of your own practice for this activity? Do you know which situations—such as a variant that does not segregate as expected—will require you to seek immediate advice from a senior Clinical Scientist or Clinical Geneticist?
• How are you feeling about embarking on this activity, given that these results 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 distinguish a true low-level mosaic variant from background noise in a Sanger trace?
• Identify the specific insights you hope to gain regarding the ethical and legal dimensions of cascade testing, particularly concerning informed consent and the implications for the wider family.
• In what ways do you anticipate this experience will improve your ability to translate technical laboratory 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 report writing to ensure your approach is building upon earlier feedback?
• Which specific information sources—including the original index case report to verify genomic coordinates, the National Genomic Test Directory to confirm eligibility, and the family’s clinical phenotype—have you reviewed to ensure your approach to cascade testing is accurate and directly addresses the referring clinician’s specific question?
• What steps have you planned to ensure clarity on the local SOPs for confirming or excluding a familial condition through segregation analysis?

In action

During the activity, did anything unexpected occur?

• What surprises or deviations are you noticing while analysing Sanger electropherograms for known familial variants?
• How are you managing traces with poor signal-to-noise ratios or baseline interference that hinder the definitive exclusion of a variant?
• How are you addressing results where a familial variant does not segregate as expected or contradicts the reported clinical phenotype?
• In what ways are you resolving ambiguities in index case reports or nomenclature that complicate targeted assay verification?
• How are you handling complex family dynamics or consent issues (e.g., unconfirmed index case status) that arise during analysis?

How are you reacting to the unexpected development?

• How is the situation leading you to re-verify genomic coordinates or pedigree structures in the moment?
• How are you utilizing raw sequencing data to distinguish true low-level variants from technical artefacts?
• How are you identifying the specific point where you must consult senior specialists to discuss the ethical implications of discordant family results?
• Which variant-specific databases (e.g., ClinVar or CFTR2) are you checking for new evidence that may have emerged since the original report?
• How are you feeling, and is the complexity of the case affecting your confidence in translating technical data into a clear report?

What was the conclusion or outcome?

• How effectively are you working within your scope of practice, and when do you determine that senior or multidisciplinary input is required?
• What insights are you gaining regarding identifying subtle mosaicism or mastering techniques to explain complex recurrence risks?
• In what ways are your real-time decisions ensuring the final report provides necessary clarity and actionable management recommendations for the family?

On action

What happened?

• How would you summarise the key points of the experience, specifically the types of cascade testing performed (predictive, carrier, or family studies) and the specific genetic conditions involved?
• What specific technical or clinical details felt most important during the process, such as interpreting complex Sanger electropherograms, performing segregation analysis, or verifying the original index case findings?
• What ‘reflect-in-action’ moments did you notice where you had to adapt as the situation unfolded—for example, by pausing to re-verify nomenclature upon identifying an unexpected result or a trace with high baseline noise?
• How did you feel during the experience, particularly when handling cases with high emotional impact and significant clinical implications for the patient and their extended family?

How has this experience contributed to your developing practice?

• What specific knowledge or skills did you develop regarding the application of testing strategies for familial disorders and the use of bioinformatic tools to investigate the clinical significance of variants?
• How did this experience improve your ability to analyse, interpret, and report results while adhering to best practice guidelines for sensitive testing scenarios?
• In what ways did your real-time decisions—such as seeking advice on the ethical implications of a discordant result—influence the final report and the management recommendations provided?
• Identify any challenges you experienced (e.g., managing limited clinical data or ambiguous pedigrees) and how you reacted to them—did this affect your ability to deal with the situation effectively?
• 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 the experience of performing these meticulous analyses relate to the requirements for your future post-programme practice as a Clinical Scientist?

What will you take from the experience moving forward?

• What areas for continued development have you identified, such as a need for further training on complex inheritance patterns, mosaicism detection, or the legal and ethical dimensions of cascade testing?
• How will you apply the learning from this activity to your routine practice—for instance, by more systematically cross-referencing index case reports or checking standard reporting templates before drafting?
• What specific ‘next steps’ will you now take to consolidate your learning, such as further study of specific familial conditions or attending a variant interpretation committee meeting?
• What support or resources (e.g., expert mentorship, access to specialist familial databases, or further MDT attendance) do you need to further develop your expertise in this field?

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 reviewing the ethical and legal dimensions of prenatal diagnosis or mastering HGVS nomenclature for complex sequence changes?
• How has your perspective on interpreting Sanger sequencing for predictive or carrier testing evolved as you have encountered a broader range of clinical pedigrees and conditions (e.g., CF, SMA, or Huntington’s Disease) beyond your initial training cases?
• In what ways has discussing with peers or clinical geneticists about challenging family cases—such as those involving discordant segregation or unexpected findings—changed your view on how to assign clinical significance?
• Are you now ready to demonstrate this new learning in practice when navigating the technical and emotional complexities of high-stakes presymptomatic testing results?

How have these experiences impacted upon current practice?

• How has the accumulated learning from performing segregation analysis and interpreting familial variants supported your preparation for observed ‘in-person’ assessments, such as Case-Based Discussions (CBDs) regarding testing strategies for patients with a family history?
• How has your practice in integrating detailed pedigree information with molecular findings developed and evolved over time to ensure you provide a clear and accurate diagnosis for the extended family?
• In what ways are you now more confident in recognising the limits of your own professional scope of practice, and can you identify specific instances where you more decisively escalate a case for senior review due to complex ethical or interpretative considerations?
• How has your current practice in writing sensitive clinical reports been enhanced by this experience, and can you identify instances where your foundational knowledge of Mendelian inheritance has informed your problem-solving in unrelated genomic cases?
• How will your understanding of the technical limitations of Sanger sequencing (e.g., identifying low-level mosaicism or baseline noise) help you evaluate and adopt new technologies, such as whole exome sequencing in family trios, in the future?

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.