SPR L10 Genetic Testing and Genetic Counselling Flashcards Preview

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Flashcards in SPR L10 Genetic Testing and Genetic Counselling Deck (41):

Genetic Testing


  • Understand the distinction between genetic screening and genetic testing
  • Be aware of the differences and similarities between diagnostic, presymptomatic, carrier and susceptibility genetic testing
  •  Be aware that ‘genetic tests’ can include clinical examination, metabolite assays and imaging as well as analysis of nucleic acid
  • Be aware of the main methods for sampling genetic material for prenatal diagnosis
  • Be able to interpret a standard genetics laboratory report (cytogenetic and molecular genetic)
  • Know where to get genetic information and understand that this should be provided to families

Genetic Counselling

  • Be familiar with the aims, methods and practice of genetic counselling
  • Be aware of the impact of genetic diagnosis on the extended family
  • Understand the principles of risk estimation in Mendelian disease
  • Be able to communicate the concept of risk in a manner that can be understood by a patient
  • Recognise situations where it is important to obtain genetic information and advice and be able to describe ways of obtaining these
  • Know how to obtain current information about scientific and clinical applications of genetics, particularly from specialised genetics services
  • Know when and how to make relevant referrals to the specialised genetics services 


Define Genetic Counselling

to help individuals understand the nature of the genetic disorder, its transmission and the options open to them in management and family planning


What are the 3 main steps in genetic counselling?

  • making an accurate diagnosis
  • describing the consequences of the disorder, the probability of developing and transmitting it
  • discussing the ways in which this may be prevented and managed


Genetic counselling

you should learn to...

  • present all relevant options fairly, accurately and non-coercively
  • be aware of the dilemmas posed by confidentiality when relatives are found to be at risk for a serious disease
  • appreciate the implications that genetic information can have for a person’s self-image, family relationships, social status etc.


Diagnosis and genetic counselling should be given...

  • in private
  • in person
  • both partners present or with a supporter
  • sensitivity, respect, compassion, understanding, honesty
  • time
  • without jargon, using positive, sensitive language
  • contact details of relevant support groups
  • offer follow-up meeting to answer new questions
  • offer emotional/psychological counselling

(Following a visit to the genetic clinic we always send out a letter to the family outlining what was discussed especially any risks and actual figures)


In genetic counselling, aside from the impact upon the patient, what needs to be considered?

Impact on extended family


Genetic Testing

Remember before we do any genetic test we always take consent

Outline Genetic Testing

  • Identifying Patients
    • family history 
    • testing criteria 
    • conditions in specialities
  • Organising Test/Management
  • Communicating Results (and their implications)
    • Lab techniques
    • Info about conditions
    • Modes of inheritance


  1. What is Genetic Screening?
  2. Give an example

  1. •Testing a group of people or population to identify individuals at high risk of having or passing on a specific genetic disorder

  2. Newborn screening for cystic fibrosis in all babies Carrier testing for Tay Sachs disease in the Ashkenazi Jewish population.    


Example of Genetic Screening: Newborn screening for genetic disorders in the UK

What is screened for?

  • PKU
  • Cystic fibrosis
  • Galactosaemia
  • Haemoglobinopathies


Diagnostic test 

  1. What is diagnositic testing used to do?
  2. Give an example

  1. to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms.
  2. E.g. checking chromosomes if a baby looks clinically like Down Syndrome


Carrier testing

  1. What is this used to do?
  2. What is it most useful for determining?
  3. Why is this not offered to children in general?
    1. What choices are removed?

  1. to determine if someone carries a single copy of an altered recessive gene OR For X-linked disorders if a female carries a single copy of an altered X chromosome gene
  2. risk to offspring and making reproductive decisions
  3. this information is really only of benefit in making reproductive decisions and will not influence their care
    1. choice of whether to undergo carrier testing or not and choice as to whether to share this information with other family members or not.



Presymptomatic test

  1. What is this also known as?
  2. What is it used to do?
  3. Give examples
  4. What is required for HD testing?
  5. Again, what is the general rule with children?

  1. a predictive test
  2. To make a genetic diagnosis of a late-onset disorder in someone who is at risk of developing the disorder but does not yet show the clinical features
  3. Huntington disease, breast cancer
  4. extensive counselling
  5. generally don't offer presymptomatic testing - If this is a condition such as breast cancer which will not affect them until later adult life then we wait until they are old enough to give their own informed consent.


Cytogenetics (chromosome analysis)

  1. How did this used to be done, how is it done now?
  2. What are the clinical indications for chromosome analysis?

  1. karyotyping - now microarray


  • Diagnosis of unknown chromosome anomaly in an individual with a pattern of mental retardation, congenital anomalies, dysmorphic features and/or aberrant growth
  • Suspected chromosomal diagnosis e.g.
    • Down syndrome (trisomy 21)
    • Klinefelter syndrome (47, XXY)
  • Check chromosomes in POC of recurrent miscarriage
  • Infertility
  • Family history of chromosome rearrangement e.g. translocation
  • Leukaemia


Cytogenetics (chromosome analysis)

When should this be carried out on Children and Young people?

  • Everyone with a learning disability or developmental delay
  • Suspected chromosomal diagnosis e.g. Down syndrome (trisomy 21),Klinefelter syndrome (47, XXY)
  • Multiple congenital anomalies
  • Babies or children with dysmorphic features
  • Short stature
  • Delayed puberty


Cytogenetics (chromosome analysis)

When should this be carried out on Adults?

  • Everyone with a learning disability
  • Infertility (both partners)
  • Parents of a stillborn baby with abnormal features if a chromosome result not available from the baby
  • At risk individuals if there is a familial balanced translocation


Cytogenetics (chromosome analysis)

Who doesn't require this analysis?

  • The clinically normal parents of a child with a trisomy e.g. Down’s Syndrome
  • The parents of a clinically normal stillborn baby
  • Someone with a known single gene disorder e.g. Cystic fibrosis NF unless there are other clinical features


Cytogenetics (chromosome analysis)

  1. How did this used to be carried out?
    1. How?
  2. What as replaced this technique?
    1. What can it not detect however?

  1. standard karyotyping
    1. Sample sent to genetics for karyotype, 

      clinical scientists looked down the microscope to look for missing or extra pieces of chromosome

  2. CGH microarray
  3. cannot for example detect balanced rearrangements - Karyotyping will still have some role as it therefore


(Karyotyping picked up abnormalities in 1-3% of children with learning disability)


Cytogenetics (chromosome analysis)

What does Array CGH involve?

Array CGH compares an individual’s DNA with a control DNA sample and identifies differences between the two sets of DNA. In this way, deletions or duplications (imbalances) in the indvidual’s DNA can be identified. From this, the gene content of any such imbalance can be established.


Cytogenetics (chromosome analysis)

  1. What is it the first line test for?
  2. What is the pick-up rate?
  3. What does the sample need to be in?

  1. developmental delay, dysmorphic children etc
  2.  10-15%
  3. Sample needs to be in EDTA


Molecular Genetic Tests

What are gene tests useful for?

  • Diagnosis
  • Treatment
  • Prognosis and Management
  • Presymptomatic Diagnostic Screening
  • Genetic Risk Assessment 


Molecular Genetic Tests

When should a genetic test be carried out?

  • A firm diagnosis of a disorder in which the genetic analysis is available (e.g. a case of Cystic Fibrosis confirmed by sweat test)
  • Diagnosis in a condition cause by readily analysed mutations in a gene (e.g. triplet repeat expansions in Huntington disease or Myotonic dystrophy)
  • A previously identified mutation in a relative
  • High probability of a mutation being present in the individual in a known gene (e.g. a young woman affected by breast cancer meeting NICE high risk criteria for BRCA1/2 testing


Chromosome Testing Vs Molecular Genetic Testing

  1. Outline how the two differ (simply)
  2. Describe how some conditions can be tested for quicker than others
  3. What explains the variation in availability and costs of tests, and also the reporting time?

  1. Looking at chromosomes is a bit like look at a book shelf to see if any books are missing.

    Looking at single gene disorders is like seeing if there is a spelling mistake anywhere in any of the books

  2. For some diseases the gene mutation is always/usually in the same place so we can quickly test the hot spots e.g. cystic fibrosis.  In other conditions it can be anywhere within the gene and we have to do gene sequencing which is expensive and time consuming e.g. BRCA1.      

  3. Some genes are quite small – finding a gene mutation in one of them is like proof-reading The Sun                                                                                Other genes are enormous – finding a mutation here is like proof reading the entire Encyclopaedia Britannica



Genetic testing is very different for NFI and NFII 

  1. How is a diagnosis of NF1 made, what impact does gene testing have?
    1. In some rare circumstances there may be a role in genetic risk assessment, give examples
  2. Describe the role of gene testing in NFII

  1. Diagnosis is made clinically Gene testing does not affect treatment, The genotype does not necessarily predicts the clinical outcome. As clinical signs are evident early in life no role for predictive genetic testing
    1. e.g. prenatal diagnosis, or atypical cases
  2. Gene testing may be necessary to make the diagnosis in individuals who show some suggestive features e.g. acoustic neuroma.  Many will have little in the way of visible skin features - Genetic testing may influence treatment and management.  In the UK there is a clearly defined protocol for the follow-up of individuals affected with NFII



Will a specific molecular diagnosis affect treatment?

  1. This criterion will become more important as...
  2. Give an example


  1.  as more diseases become treatable.
  2. Current example is MPS I.  If the mutation shows it is Hurler Type, treatment of choice is a bone marrow transplant.  If it is Hurler Scheie or Scheie it would be enzyme replacement therapy.


Prognosis and Management

​ Outline the link between genetic testing and prognosis and management

Give an example

Is there evidence in this disease that a specific molecular sub-type will affect prognosis and management to a significant extent?

In other words - will the result significantly affect the lifestyle choices of the patient or the family?  (e.g.: avoiding smoking for ZZ alpha 1 antitrypsin genotype).


Presymptomatic Testing

Presymptomatic Diagnostic Screening

What are the important questions that need to be asked?

  • Will a positive molecular result accurately predict future disease and alter management?
  • Will a negative molecular result be definitive (i.e.: further tests do not need to be carried out)?


Presymptomatic Testing

Predictive Testing

  1. How is this done, for whom?
  2. Who is this not usually done in? Why?

  1. Usually done with fairly strict protocols - Can be for conditions where no real intervention is possible but testing may help individuals to make life choices and prepare for the onset of disease e.g. Huntington’s OR where Intervention may be possible e.g. BRCA1 testing or FAP
  2. not usually done in children - For someone to be able to give informed consent to such a test they need to be able to fully understand the implications of the result


Presymptomatic Testing

Testing for Cancer

  1. How is it decided who gets tested?
  2. Why is testing time consuming and costly?
  3. What if a mutation is found?

  1. Nationally agreed protocols to decide who gets tested e.g. manchester scoring system
  2. large genes lots of private mutations
  3. other family members can be offered predictive testing


Genetic Risk Assessment

What are the question that need to be asked?

  • Will molecular diagnosis in the affected person reduce the needs for tests in the rest of the family?
  • Will molecular diagnosis resolve the mode of inheritance? (e.g.: HMSN)
  • Will molecular diagnosis provide a means of pre-natal  diagnosis or carrier detection?
  • Will molecular diagnosis allow pre-symptomatic testing for  other family members?


Genetic Risk Assessment


  1. What is this?
  2. What can now be identified?

  1. X-linked lissencephaly with ambiguous genitalia - Severe neurological outcome

  2. Can now identify at risk female carriers


Genetic Risk Assessment

Making a genetic diagnosis does not always require a molecular genetic test - what else may be used?

  • imaging
  • other laboratory testing e.g. haemoglobin electrophoresis for sickle cell disease


Clinical Scenario


  • Baby referred with macrocephaly
  • History of ENT infections
  • You suspect he has Hurler disease MPS I

What do you do?

  • don’t do a genetic test first
  • send urine to see if it contains GAG’s
    • If positive you send a sample of blood for the alpha iduronidase assay
    • If the enzyme is low this will confirm the diagnosis
  • You then do the gene test because this will enable you to offer carrier testing to the extended family


Panel tests

  1. What are labs starting to offer?
  2. What will these enable patients to be tested for?
    1. What is an advantage?
  3. What are these tests useful for?
    1. Give examples
  4. What are the cautions with these tests?

  1.  tests for a panel of genes that may cause very similar clinical features by using next generation sequencing.
  2. a large number of genes at one time
    1. Less time consuming and less expensive than repeated single gene tests
  3. Panel tests are useful for conditions where a large number of genes can give a very similar clinical picture


      53 gene early onset epilepsy panel

      106 gene cataract panel

  4. Gene coverage may not be as good as classical sanger sequencing, May pick up unexpected findings, Some of the genes tested for may have other effects that the patient was not expecting, Will need good counselling and consent procedures

Clinicians will need to decide how much information they want from the test and how much they wish to communicate to patients and thus perform the consent process accordingly


Prenatal diagnosis

Ultrasound scanning

  1. What can this be used to diagnose?
  2. What is it particularly good for?
  3. When do most women have a routine anomaly scan at?

  1. genetic conditions
  2. at ~20 weeks
  3. detection of autosomal recessive polycystic kidney disease.
  • Scans may be perceived as ‘ the first baby picture’ for the album
  • They are in reality a test to see if something is wrong with the baby


Prenatal diagnosis


  1. When is this performed from?
  2. How is it carried out?
  3. When is it most commonly used?
    1. What else can be performed?
  4. What are the risks?

  1. 15 weeks
  2. Remove 5-10 ml fluid - Can culture amniocytes for karyotyping or interphase FISH or molecular testing
  3. in cases of increased maternal age
    1. Can perform metabolic assays
  4. Risk of miscarriage ~1%


Prenatal diagnosis

Chorion Villus Sampling

  1. When is this performed from?
  2. How is it carried out?
  3. What is it used for?
  4. What are the risks?

  1. Performed at 10-12 weeks

  2. Involves sampling chorion tissue

  3. In Belfast used mainly for molecular or metabolic tests - karyotyping may also be carried out.

  4. Risk of miscarriage ~2%


Pre-implantation Genetic Diagnosis

  1. What is this?
  2. What knowledge is needed?
  3. Where is it offered?

  1. a technique for creating an embryo which will not be affected with a particular disorder. Blastomere biopsy - unaffected embryos are then reimplanted.
  2. Need to know the genotype i.e. the genetic mutations within the family
  3. Offered in highly specialist centres - Strict criteria for funding


Bad reasons for doing a Gene Test

What are these?

  • Because I read about it in a journal
  • Because I don’t trust my clinical skills
  • Because the patient knows there is a gene test
  • To complete my battery of tests – they’ve had everything else they might as well have a gene test


Things to avoid

What are these?

  • Scatter gun genetic testing ‘Please test for genes x, y, z’
  • Asking us to do a gene test to exclude a certain condition which you don’t think the patient has. Use your clinical skills.
  • Most laboratories have quite strict testing criteria and will reject samples which do not meet those criteria


Good Reasons To Do a Gene Test

What are these?

  • Diagnosis
  • Treatment
  • Prognosis and Management
  • Presymptomatic Diagnostic Screening
  • Genetic Risk Assessment 


What is the UKGTN?

The United Kingdom Genetic Testing Network assesses gene tests offered in genetic labs for their clinical utility.  If approved they go on the list of approved tests for which commissioners have agreed that funding should be provided.