Prenatal Genomics —
Training activity: 6

Details

Analyse, interpret and report the results of cases referred due to a family history of a genomic condition, to include:

• Segregation analysis
• Targeted molecular tests

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.

Considerations

• Principles of the assays, including sequencing, MLPA and chromosome analysis
• Best practice guidance
• Local and national guidance
• Quality control, including IQC, and EQA
• Nomenclature
• Interpretation of results
• Variant classification
• Reflex testing options
• Disease mechanism
• Test sensitivity and limitations, including mosaicism, and maternal cell contamination
• Impact of confined placental mosaicism and fetal mosaicism on diagnosis
• Local SOPs
• Local format for reporting
• Health and safety
• Segregation analysis and risk estimation

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?

• Identify what is expected of you: to accurately analyse, interpret, and report results for prenatal cases based on a family history of a genomic condition, specifically involving segregation analysis and targeted molecular tests.
• Consider how the learning outcomes apply, specifically concerning applying appropriate testing strategies for family history, interpreting genomic variants, and reporting prenatal genomic findings.
• What does successful interpretation look like, specifically involving accurate segregation analysis and interpreting targeted molecular results in the context of familial inheritance and potential recurrence risk?
• Discuss with your training officer to gain clarity on the standards for analysing family history information, performing segregation analysis, interpreting targeted molecular results, and reporting implications for the family.

What is your prior experience of this activity?

• Think about what you already know about interpreting targeted molecular test results, understanding principles of Mendelian inheritance, and performing segregation analysis.
• Consider possible challenges you might face, and think about how you might handle them, e.g., obtaining and interpreting detailed family history, performing accurate segregation analysis with complex pedigrees, or considering the sensitive implications of results for other family members.
• Recognise the scope of your own practice for this activity i.e. know when you will need to seek advice or help, and from whom, e.g., with complex family histories, novel variants, or sensitive discussions about implications for relatives.
• Acknowledge how you feel about embarking on this training activity, about working with cases that have significant implications for multiple family members.

What do you anticipate you will learn from the experience?

• Consider the specific skills you want to develop – drawing upon previous experiences of similar activities, e.g., proficiency in performing and interpreting segregation analysis, and analysing targeted molecular test results in a familial context.
• Identify specific insights you hope to gain from engaging with the activity, e.g., understanding the ethical and legal considerations surrounding familial testing, the importance of segregation analysis in confirming inheritance, and learning how to integrate molecular findings with clinical and family history information.

What additional considerations do you need to make?

• Consult actions identified following previous experience with familial cases or targeted molecular testing.
• Identify important information you need to consider before embarking on the activity, e.g., reviewing principles of inheritance, standard reporting templates for familial cases, and the ethical and legal aspects of pregnancy and the unborn foetus in this context.

In action

Is anything unexpected occurring?

• Are you noticing anything surprising or different from what you anticipate during the analysis and interpretation of the familial case results?
• Are you encountering situations such as:
  • Identifying a result where the familial variant does not segregate as expected e.g., an unexpected foetal result relative to parental samples.
  • Encountering a complex family pedigree or vague family history that complicates the initial segregation analysis.
  • Identifying an unrelated variant of uncertain significance (VUS) during the targeted molecular test, despite expecting only the known familial variant.

How are you reacting to the unexpected development?

• How is this impacting your actions? For example, are you responding to the situation appropriately? Are you adapting or changing your approach to analysis and reporting?
• Consider the steps you are taking in the moment, such as:
  • Immediately reviewing the pedigree or original family report to verify inheritance patterns and confirm the segregation of the known familial variant.
  • Consulting external databases or interpretation guidelines (e.g., variant databases) for unexpected variants or complex inheritance patterns.
  • Seeking immediate advice from a senior colleague regarding the interpretation of a complex familial case or the ethical implications of reporting incidental findings or VUS.
• How are you feeling in that moment? For instance, are you finding it difficult to adapt the reporting focus to address the clinical question while remaining sensitive to the implications for the extended family?

What is the conclusion or outcome?

• Identify how you are working within your scope of practice. For example, are you successfully confirming or excluding the familial condition through meticulous segregation analysis? Or are you needing support because the case involves novel ethical or interpretative considerations (e.g., dealing with variable penetrance)?
• What are you learning as a result of the unexpected development? For example, are you learning a specific technique for integrating complex family history and molecular findings into a coherent prenatal report, ensuring clarity on recurrence risk?

On action

What happened?

• Begin by summarising the key points of the experience of analysing and interpreting the results of familial genomic cases, e.g., the key familial genomic conditions for which you analysed results.
• Consider specific events, actions, or interactions which felt important, such as performing segregation analysis on a complex pedigree or analysing targeted molecular test results in the context of inheritance.
• Include any ‘reflect-in-action’ moments, where you adapted to the situation as it unfolded, for instance, consulting external databases during interpretation of an unexpected targeted molecular test result or VUS. How did you feel during this experience?

How has this experience contributed to your developing practice?

• Identify what learning you can take from this experience regarding familial cases, e.g., improving your ability to interpret targeted molecular test results and perform segregation analysis within a family context.
• What strengths did you demonstrate e.g., accurate interpretation of molecular findings? What skills and/or knowledge gaps were evident e.g., difficulty integrating complex family history information or reporting implications for other family members?
• Compare this experience against previous familial analysis activities – were any previously identified actions for development achieved? Has your practice in analysis and reporting improved?
• Identify any challenges you experienced, e.g., integrating complex family history with molecular data or reporting findings with sensitive implications for extended family, and how you reacted to these. Were you able to overcome the challenges?
• Identify anything significant about the activity, such as seeking advice on the ethical considerations of reporting incidental findings in a prenatal familial case, to ensure you were working within your scope of practice.
• Acknowledge any changes in your own feelings now you are looking back on the experience.

What will you take from the experience moving forward?

• Identify the actions or ‘next steps’ you will now take to support the assimilation of what you have learnt, including from any feedback you have received, e.g., reviewing resources on specific familial genomic conditions or improving integration of family history data.
• What will you do differently next time you analyse a familial case, e.g., systematically checking the pedigree structure against the predicted inheritance pattern before proceeding to the molecular data? Has anything changed in terms of what you would do if you were faced with a similar situation again?
• Do you need to practise any aspect of the activity further, e.g., further training on segregation analysis techniques for complex inheritance patterns?

Beyond action

Have you revisited the experiences?

• Have you reviewed your actions from your previous reflections for this activity? What specific actions did you previously identify you would need to take to improve your practice related to performing segregation analysis or interpreting targeted tests?
• Have you completed these previously identified actions? For example, if you planned to review the ethical and legal dimensions of prenatal diagnosis, how did completing this action impact your approach to reporting sensitive familial findings?
• Engage in professional storytelling with peers, near peers, or colleagues about complex familial pedigrees or challenging interpretations. Has discussing the ethical and reporting challenges related to incidental findings or VUS discovered during targeted familial testing changed your perspective on clinical reporting?
• Compare these experiences with analysing familial cases in other genomic areas (e.g., cancer predisposition). What observable practices regarding the integration of family history information have you assimilated?

How have these experiences impacted upon current practice?

• Consider how the accumulated learning from performing or reflecting on familial case analysis will support you in preparing for observed ‘in-person’ assessments for the module, such as Case-Based Discussions requiring application of appropriate testing strategies for patients with a family history.
• How has your understanding of integrating family history with genetic data for segregation analysis evolved over time?
• How have subsequent experiences e.g., participating in multidisciplinary discussions or clinical experiences changed your perspective on the clinical implications of familial findings and the importance of clear reporting for family members?
• As new technologies like whole exome sequencing in family trios become more common, how will your foundational understanding of segregation analysis and targeted testing principles prepare you to interpret and report on more complex familial findings in the future? What clear actions for continued development have you identified to enhance your expertise in familial genomics?

Relevant learning outcomes

#	Outcome
# 3	Outcome Apply appropriate testing strategies to patients with a family history of a genetic disorder.
# 4	Outcome Interpret chromosomal rearrangements, including implications for recurrence risk and future testing.
# 5	Outcome Interpret genomic variants, including copy number changes and investigate the clinical significance of variants using bioinformatic tools using best practice guidelines.
# 6	Outcome Interpret and report prenatal genomic findings, including appropriate recommendations for patient management.