Module - Adult Genetic and Genomic Disorders (SLS422)

STP

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.

Work-based 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.

Work-based Competencies


Learning outcome Title Knowledge
1 1

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
  • The principal referral reasons that would indicate testing for each of the conditions under investigation.
  • The clinical, scientific basis for the repertoire of genetic testing available to investigate the common range of clinical referrals.
  • Ethical issues associated with patient consent including predictive testing.
  • The need for consent before testing and the implications for relatives following a positive test result.
  • The use of this test for other referral reasons (e.g. FRAXA).
  • The clinical utility of genetic testing in patients with infertility, neurogenetic and/or cardiomyopathy.
  • The range of tests suitable for patients presenting with or having a family history of particular neurological or muscular symptoms (e.g. muscle weakness, myotonia, chorea, foot drop).
  • The genetic alteration/genes associated with a range of adult onset neurological and muscular disorders (e.g. HD, FA).
  • The need for pre and post-test counselling for individuals undergoing predictive (e.g. for HD) and carrier (e.g. Friedreich ataxia) testing.
  • The utility of Next Generation Sequencing for this group of patients.
2 1

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)
  • The principal referral reasons that would indicate testing for each of the conditions under investigation.
  • The clinical and scientific basis for the repertoire of genetic testing available to investigate the common range of clinical referrals.
  • Ethical issues associated with patient consent including predictive testing.
  • How to recognise this type of genetic testing in relation to other clinical referrals and laboratory testing.
  • The range of genetic alterations/genes responsible and the tests suitable for patients presenting with cancer.
  • The need for pre and post-test counselling for individuals with a family history of cancer.
  • Application of appropriate methodologies that can be used to identify different classes of mutation.
  • The application of pre-screening tests to select patients who require full mutation analysis, e.g. MSI and IHC in colorectal cancer.
  • The utility of Next Generation Sequencing for this group of patients.
3 2

Perform whole genome analysis for patients referred for infertility.

  • Whole genome analysis from patients with infertility.
  • Use of ISCN.
  • Best practice guidelines and QA for chromosome analysis (internal and external).
4 4,5

Interpret results from chromosomal analysis for patients referred for infertility.

  • Interpretation of results from chromosome analysis using relevant online databases and literature.
  • Perform segregation analysis for patients with balanced translocations and assess the risk of affected offspring.
  • How to critically appraise relevant literature and databases.
  • The need for further genetic testing, e.g. molecular analysis to detect Y chromosome deletions.
5 3

Perform a PCR-based test to detect common CFTR mutations.

  • The principles of the assay used and the limitations of the test.
  • Identification of samples that require repeating or further investigation.
  • Best practice guidelines and QA (both internal and external).
6 4,5,6

Analyse, interpret and report on the most common CFTR mutations.

  • The relevance of polyT tract variants.
  • The implications for other family members of identifying a CFTR mutation in an infertile male.
  • The implications of the genetic tests (including ethical, legal and social implications) for the effective management of this group of patients.
  • The molecular pathogenesis of CFTR mutations in relation to 
  • congenital bilateral absence of the vas deferens (CBAVD).
  • The counselling issues associated with this referral group.
  • Implication of the CF result in other patient pathways, e.g. diagnostic testing.
  • The integration of targeted mutation analysis associated with screening protocols, with genetic testing for the same disease in other care pathways.
7 5,6

Interpret FMR1 analysis in relation to premature ovarian failure (POF).

  • The technical basis of detecting FRAXA premutation alleles.
  • The implications for other family members of identifying a FRAXA premutation in a patient with POF.
8 5,6

Analyse and interpret the results of laboratory tests to detect triplet repeat expansions.

  • The concept of phenocopies that might cause similar symptoms, e.g. HD and the importance of these in interpreting the results of predictive testing and in suggesting further diagnostic tests.
  • The difference between diagnostic and predictive/carrier testing and the ability to interpret and report results accordingly.
9 4,5

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.

  • Principles underpinning the technology used including its limitations.
  • Principles of different methods for library preparation.
  • Principles of different sequencing technologies.
  • Quality parameters.
  • Basis upon which variants identified in the germline are classified according to their pathology.
  • Validation and verification of findings.
  • The need for confirmation testing.
  • Panels vs whole exome/genome analysis.
  • Principles of data storage.
  • How to assess the significance of unclassified variants using appropriate bioinformatic tools.
  • Use of relevant literature and databases to interpret results.

 

10 5,6

Analyse and interpret the results for predictive or confirmation testing.

  • Use of automated software to analyse data.
  • Use of HGVS to record sequence variation.
  • Recognition of the appropriate quality standards for the results obtained.
11 5,6

Prepare a range of reports relevant to the referral reason.

  • Recognising all tests have been completed to a satisfactory standard for the referral reason.
  • All information has been validated as correct.
  • Selection of correct report template for referral reason.
  • Recommendations for further referral (e.g. clinical genetics). Identify the requirements for any follow up testing, the testing methods available and the appropriate choice of test. Describe any limitations.
  • Use of correct scientific and clinical terminology.
  • Use of relevant databases and literature in the interpretation of results.
  • Communication of complex scientific information to clinicians and patients.
  • Best practice guidelines compared with laboratory practice and any differences between the two.
  • How to identify pertinent EQA schemes; their role and practice, how these are incorporated into laboratory practice and ISO standards for lab participation in EQA schemes.

Work-based assessment


Complete 3 Case-Based Discussion(s)
Complete 3 of the following DOPS and/or OCEs
Type Title
DOPS 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
OCE 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