Adult Genetic and Genomic Disorders

Module details

Title

Adult Genetic and Genomic Disorders

Type

Specialist

Module code

SLS422

Credits

15

Requirement

Compulsory

Aim of this module

This module will provide the trainee with knowledge and understanding of the role and application of genetic and genomic testing in the diagnosis  and management of patients with adult onset genetic and genomic disorders, as well as the implications for other family members.

 

The content for this module will focus on (as exemplars) patients who present with features of: inherited peripheral neuropathies, neurogenetic conditions, hypertrophic and dilated cardiomyopathy, infertility (using cystic fibrosis and chromosome disorders), Fragile X testing for premature ovarian failure, inherited breast cancer and Lynch syndrome, Huntington’s disease, myotonic dystrophy and Friedreich ataxia.

Competencies

#	Learning outcome	Competency	Action
# 1	Learning outcome 1	Competency Select the correct genetic test(s) for the patient samples referred for adult conditions using the following exemplars: Hypertrophic and dilated cardiomyopathies Huntington disease Fragile X (FRAXA) Friedreich ataxia (FA) Cystic fibrosis CMT1A/HNPP	Action View
# 2	Learning outcome 1	Competency Select the correct genetic test(s) for the patient samples referred for adult conditions using the following exemplars: Breast cancer Lynch syndrome Familial adenomatous polyposis (FAP)	Action View
# 3	Learning outcome 2	Competency Perform whole genome analysis for patients referred for infertility.	Action View
# 4	Learning outcome 4,5	Competency Interpret results from chromosomal analysis for patients referred for infertility.	Action View
# 5	Learning outcome 3	Competency Perform a PCR-based test to detect common CFTR mutations.	Action View
# 6	Learning outcome 4,5,6	Competency Analyse, interpret and report on the most common CFTR mutations.	Action View
# 7	Learning outcome 5,6	Competency Interpret FMR1 analysis in relation to premature ovarian failure (POF).	Action View
# 8	Learning outcome 5,6	Competency Analyse and interpret the results of laboratory tests to detect triplet repeat expansions.	Action View
# 9	Learning outcome 4,5	Competency Analyse and interpret the results of next generation sequencing for a panel of genes related to adult onset disorders, e.g. genes associated with breast cancer, Lynch syndrome or cardiomyopathy.	Action View
# 10	Learning outcome 5,6	Competency Analyse and interpret the results for predictive or confirmation testing.	Action View
# 11	Learning outcome 5,6	Competency Prepare a range of reports relevant to the referral reason.	Action View

Assessments

You must complete:

• 3 case-based discussion(s)
• 3 of the following DOPS/ OCEs:

Analyse chromosomes and use correct nomenclature	DOPS
FISH analysis using microscopy	DOPS
Processing samples for FISH	DOPS
Analyse results of MLPA analysis	DOPS
Interpret and report MLPA data	DOPS
Perform sequence analysis using relevant software	DOPS
Analyse the results of CF testing	DOPS
PCR amplification of a triplet repeat	DOPS
Perform basic risk calculation	DOPS
Analyse results generated by Next Generation Sequencing	DOPS
Use bioinformatic tools to interpret the clinical significance of a sequence variant	DOPS
Prepare a clinical report for a patient referred with a late onset condition unrelated to cancer	DOPS
Prepare a clinical report for a patient referred with a personal and or family history of cancer	DOPS
Prepare a clinical report for a patient referred with infertility	DOPS
Prepare a clinical report for a patient referred for presymptomatic testing for a late onset condition unrelated to cancer	DOPS
Prepare a clinical report for a patient referred for presymptomatic testing for an inherted cancer	DOPS
Prepare a clinical report for an adult patient referred with a neuromuscular disorder	DOPS
Assess microsatellite results from a colorectal sample for Lynch syndrome	DOPS
Participate in an MDT meeting with other healthcare professionals	OCE
Take a patient history can be undertaken in virtual patient environment	OCE
Discuss patient results with a healthcare professional telephone or in person	OCE

Learning outcomes

1. Apply appropriate testing strategies relevant to patients referred for adult onset genetic and genomic disorders.
2. Perform appropriate level of whole genome analysis for patients with primary infertility.
3. Perform targeted testing for patients referred with adult onset genetic and genomic disorders.
4. Investigate the clinical significance of variants using a range of bioinformatics tools following current best practice guidelines.
5. Interpret and report the range of genetic and genomic testing relevant to these adult onset genetic and genomic conditions.
6. Perform familial follow up studies including for variants of uncertain clinical significance, showing an understanding of the presence of phenocopies.

Learning outcomes

1. Explain the clinical presentation and assessment of patients with adult onset genetic and genomic disorders.
2. Discuss and evaluate the appropriate genetic and genomic laboratory testing strategies for adult patients with genetic and genomic disorders according to current best practice.
3. Discuss the design, operation and performance of the range of genetic and genomic tests relevant to the investigations.
4. Discuss and debate the relevant clinical scientific, ethical and legal dimensions.
5. Describe the purpose and evaluate how integrated working across clinical specialisms supports patient-centred care, including the diagnosis and treatment strategies for patients and their families.

Indicative content

Clinical presentation and assessment of patients with adult onset genetic and genomic disorders

• Clinical presentation and types of inheritance, including pedigree analysis
• Importance of accurate phenotyping

 Appropriate genetic laboratory testing strategies for adult patients with genetic disorders

• Design, operation and performance of a range of genetic tests
• The principles of cost effectiveness
• Laboratory testing pathway including reflex testing
• Single gene and massively parallel sequencing strategies
• The relative merits of panel based, whole exome and whole genome analysis
• Testing methodology including limitations and sensitivity
  • PCR based methods including triplet repeats and methylation and kit based testing
  • Copy number variation detection (e.g. MLPA, chromosomal microarray, FISH and G-band analysis)
  • Sequencing – using all current methods in clinical use
  • Validate and verify results
• The importance of appropriate internal quality control and external quality assurance
• Bioinformatics for the processing of large datasets
• Exclusion testing by linked microsatellite analysis in Huntington disease
• Importance of turnaround time in the pathway of care
• Interpret archived results based on older technologies and discuss the implication and limitation of these results for the patient and family

 Clinical scientific, ethical and legal considerations

• Consent for testing and storage of patient material including deceased patients
• National guidelines for predictive and presymptomatic testing
• The importance of counselling, e.g. in predictive testing of late onset disorders such as Huntington disease and the importance of distinguishing between diagnostic and predictive test requests
• Follow-up management including prenatal testing for subsequent pregnancies
• Safeguarding vulnerable adults

 Interpretation and reporting of results to include:

• Analysis and interpretation including the relationship of the genetic alteration to the phenotype
• Proteomics for the interpretation of variants of uncertain significance
• Clinical reporting
  • Categories of genetic variation observed within these patient groups
  • The mechanisms of pathogenesis for these disorders including the difference between sporadic and inherited conditions, e.g. breast and colon cancer
  • Diagnostic and prognostic significance of genetic abnormalities found in these groups of patients
  • The use of linkage analysis and the risk of recombination to include Bayesian calculation
  • Use of standardised nomenclature to describe genetic and genomic variation
  • How to critically appraise relevant literature and databases to develop an awareness of the need for any further testing
• Role of multi-disciplinary team (MDT) meetings to aid interpretation and guidelines such as improving Outcomes Guidance and NICE guidelines

Activities

• Attend genetics clinics including a cancer genetics clinic, a pre-symptomatic clinic and a Huntington disease clinic. Review and critically reflect on the role and importance of these clinics and their interaction with the genetics laboratory service.
• Attend infertility clinics and identify at least one patient to follow through their investigation and management. Critically reflect on the experience and discuss the outcomes and the role of these clinics, including the interaction with the laboratory services with your supervisor.
• Visit an assisted conception unit and critically reflect on your experience and the nature of partnership working between the laboratory and clinical services.
• Attend a neurology clinic or multidisciplinary team meeting and critically reflect on the role of these clinics in patient care and the important aspects of partnership working with the genetics laboratory service.
• Attend a physiotherapy clinic for patients with neuromuscular conditions and follow one patient’s management. Critically reflect on the role of the genetics service in supporting patient care.
• Attend and participate in MDT meetings. Review and reflect on the role of multidisciplinary working in genetics and its importance for effective patient investigation, diagnosis and management.

 

• Observe and reflect on the laboratory processes associated with next generation sequencing.
• Observe MLPA. Review a selection of archived cases focussing on the laboratory results from earlier technology.