Rare Disease 2 —
Training activity: 6

Details

Perform risk calculations for modes of inheritance to include:

• autosomal recessive
• X-linked

Type

Developmental training activity (DTA)

Evidence requirements

Evidence the activity has been undertaken by the trainee​.

Reflection on the activity at one or more time points after the event including learning from the activity and/or areas of the trainees practice for development.

An action plan to implement learning and/or to address skills or knowledge gaps identified.

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 are the intended outcomes of the training activity?

• How will performing these calculations support your ability to analyse and interpret results and provide a safe and high-quality service?
• How do these calculations directly inform the clinical management of patients?
• What specific mathematical principles do you need to understand before starting, such as Bayesian probability or the Hardy-Weinberg equilibrium for calculating population carrier frequencies?
• Do you understand the nuances of X-linked inheritance, such as the implications of skewed X-inactivation or germline mosaicism, versus the standard carrier risks for autosomal recessive conditions?

What do you anticipate you will learn from the experience?

• What specific insights do you hope to gain regarding the integration of pedigree information with molecular genetic results to refine a patient’s risk?
• How comfortable are you with drawing a pedigree and assigning initial prior risks based on Mendelian laws?
• How do you anticipate this activity will improve your ability to communicate complex risk figures to healthcare professional colleagues in a clear and meaningful way?

What actions will you take in preparation for the experience?

• Will you review relevant textbooks or literature on genetic risk assessment? Will you consult your laboratory’s Standard Operating Procedures (SOPs) for reporting risks?
• How have you planned to ensure you understand the expected level of complexity for these calculations?
• What potential difficulties do you anticipate? For example, how will you handle incomplete family histories, reduced penetrance, or variants of uncertain significance when calculating a final risk?
• How do you feel about the professional responsibility of providing risk figures that may influence a patient’s reproductive choices or clinical surveillance?
• Under what circumstances (e.g., a highly complex family tree or conflicting data) will you seek immediate advice from a senior scientist to ensure you are delivering a safe service?

In action

What are you doing?

• How are you approaching these risk calculations, and why have you chosen a specific method such as a Bayesian calculation or the Hardy-Weinberg principle?
• What decisions are you making as you assign prior risks based on the family pedigree and incorporate conditional information, such as the number of unaffected children?
• Which aspects of the calculation feel intuitive, and which—such as adjusting for reduced penetrance or age-dependent onset—require more conscious effort?

How are you progressing with the activity?

• How effective are your current actions in arriving at a clear, accurate risk figure that can be safely reported?
• How are you managing real-time challenges, such as incomplete pedigree data, the complexities of X-linked inheritance (e.g., germline mosaicism), or integrating molecular findings with pedigree-based risks?
• What are you learning as the activity unfolds regarding how small changes in clinical assumptions can significantly impact the final risk figure?

How are you adapting to the situation?

• Which alternative approaches, such as different penetrance models or population-specific data, are you exploring if the standard Mendelian model remains unclear?
• How will you double-check your mathematical steps to ensure a safe and high-quality service?
• In what ways are you ensuring that your communication of the risk is framed clearly and is clinically meaningful for healthcare professional colleagues?
• How are you ensuring you remain within your professional scope of practice, and at what point does the complexity of the family (e.g., consanguineous loops) require specialist input from a consultant clinical geneticist?

On action

What happened?

• How would you summarise the key risk calculation scenarios you performed, such as carrier risk for siblings or offspring in X-linked pedigrees?
• Which mathematical models or principles (e.g. Bayesian analysis or Hardy-Weinberg equilibrium) did you apply to these cases?
• What was the range of results you encountered, and were the final risks high enough to warrant recommendations like prenatal diagnosis or carrier testing?
• How did you feel when managing the professional responsibility of providing figures that influence a family’s reproductive choices?

How has this experience contributed to your developing practice?

• In what ways has your ability to integrate pedigree data with molecular results to calculate refined posterior risks improved?
• How did this activity enhance your knowledge of inheritance nuances, such as germline mosaicism in X-linked conditions or reduced penetrance in recessive disorders?
• How did you successfully manage unexpected challenges like consanguinity or incomplete family histories, and how did your ‘reflection-in-action’ influence the outcome?
• How does mastering these calculations support your requirement to deliver a safe and high-quality service in your future post-programme practice?

What will you take from the experience moving forward?

• Do you require further practice with complex Bayesian factors or different penetrance models?
• What new strategies, such as a more systematic approach to reviewing pedigrees, will you adopt when drafting future clinical reports?
• Which specific ‘next steps’—such as seeking senior feedback on complex calculations or creating templates for standard scenarios—will you take to consolidate your learning?
• What support or resources (e.g. specialized risk calculation software, advanced textbooks, or expert mentorship) have you identified as necessary to further develop your expertise?

Beyond action

Have you revisited the experiences?

• How has your understanding of incorporating conditional information, such as unaffected offspring, into Bayesian or Hardy-Weinberg calculations evolved since your initial attempts?
• In what ways have you assimilated the systematic checking methods or logical frameworks observed during OTAs into your own routine practice?
• What overarching themes regarding the integration of pedigree data with molecular findings have emerged from reviewing reflections across related modules?
• How has discussing complex cases (e.g. germline mosaicism or reduced penetrance) with senior colleagues changed your perspective on assigning risk in a diagnostic setting?

How have these experiences impacted upon your current practice?

• How have these calculations supported your development of high-level clinical reasoning and report writing skills, rather than being treated as isolated mathematical tasks?
• How has your confidence grown in identifying when a referral requires a complex stratified risk approach rather than a standard Mendelian calculation?
• In what ways is this learning supporting your preparation for ‘in-person’ assessments (CBD or OCE) where you must justify specific recurrence risks to healthcare professionals?

How might these contribute towards your future practice?

• How will the ability to communicate complex probabilistic data in a clear, clinically meaningful way support your future role as a Clinical Scientist?
• Which clear steps for continued development—such as attending risk software workshops, reviewing population frequency literature, or leading MDT discussions—will you take to further your expertise?

Relevant learning outcomes

#	Outcome
# 2	Outcome Analyse, interpret and report results for diagnostic, presymptomatic and familial/carrier 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.