20-03-23 – Genetic Counselling Flashcards
Learning outcomes
- Communicate genetic information in an understandable, non-directive manner, being aware of the impact genetic information may have on an individual, family and society
- Describe the aims, methods and practice of genetic counselling
- Recognise the impact of genetic diagnosis on the extended family
- Explain the concept of risk in a manner that can be understood by a patient
What is the definition of genetic counselling?
What 3 things does the process of genetic counselling integrate?
- The Genetic Counseling Definition Task Force of the National Society of Genetic Counselors (2006):
- Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease
- 3 things the process of genetic counselling integrates:
1) Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
2) Education about inheritance, testing, management, prevention, resources and research.
3) Counselling to promote informed choices and adaptation to the risk or condition.
How is cystic fibrosis (CF) inherited?
Which race is it most common in?
What is the incidence CF in the UK?
What is the carrier frequency in the UK?
- Cystic fibrosis (CF) is Autosomal Recessive inheritance
- Most common fatal inherited disease in Caucasians
- Incidence of 1 in 2400 in UK
- Carrier frequency 1 in 23 (Scotland)
- CF results in a mutated chloride channel
Case 1
- Case 1
- One month old John referred to Clinical Genetics after newborn screening diagnosis of Cystic Fibrosis
What is the purpose of the new-born screening programme for CF?
What is screening based on?
What happens if there is a raised IRT?
When is CF suspected in testing?
When is CF confirmed?
- The new-born screening programme for CF allows identification of babies with CF to allow early treatment interventions
- It is based on heel-prick immuno-reactive trypsinogen (IRT) level
- Raised IRT - test using CF mutation kit
- CF suspected if IRT raised and one pathogenic mutation found
- CF confirmed if 2 pathogenic mutations found
Case 1: What is the basis for CF diagnosis?
- Case 1: What is the basis for CF diagnosis?
- John raised IRT x 2 - G551D / R117H
- 1 mutation on 2 different chromosomes
- G551D mutation is definitely associated with CF
Case 1: Genotype-Phenotype correlation.
How many pathogenic mutations are needed for CF to be present?
What can happen if only 1 is present?
- 2 pathogenic mutations are required for CF to be present
- If only 1 pathogenic mutation is present, someone may not have full blown CF, but a condition like CF syndrome
- We need to know how many pathogenic mutations are present so that we can start treatment asap
How does the R117H gene contribute to CF?
How does it affect CF presentation in childhood?
How do the effects of R117H vary?
- R117H is the second mutation in 1.85% of Scottish CF patients, but makes up 9% of CF mutations identified on postnatal screen
- The majority of R117H compound heterozygotes do not present with CF in childhood
- The effect of R117H varies according to Intron 8 (non-coding) splice site efficiency
Describe the effects of CFTR Intron 8 variants of the R117H gene on CF.
- The effects of CFTR Intron 8 variants of the R117H gene on CF:
- Normally in the CFTR pre-mRNA, intron 8 is spliced out to from a normal CFRT mRNA and hence normal CFTR protein
- The CFTR genotype contributes to this
- The more Ts there are consecutively in the CFTR genotype, the greater the percentage of normal CFTR proteins and vice versa
- The less Ts there ae consecutively, the more severe the phenotype will be
Case 1: outcome for John
- Case 1: outcome for John
- John has R117H/5T – He is producing a CFTR protein that doesn’t have much function due to the R117H mutation, and the 5Ts mean he is not producing much of it
- Risk of developing symptoms of CF during childhood
- What are the implications of G551D mutation (known to be a pathogenic mutation for CF)? – Ivacaftor (Kalydeco) therapy?
- Follow up through CF clinic
Case 1: Issues for the rest of the family. What is the risk to Peter?
Would cascade testing for relatives be useful?
What are the 2 options for future pregnancy?
- Case 1: Issues for the rest of the family
- What is the risk to Peter? – If he is 7 and hasn’t shown symptoms, he is probably fine
- Cascade testing of relatives – not interested in cascade as much in CF, as only 1 in 4 chance of CF if both parents are carriers
- Options for any future pregnancy:
1) Prenatal Diagnosis (PND):
* Chorionic villus sampling (CVS)
* Amniocentesis – Pre-implantation
2) Genetic Diagnosis (PGD)
Case 2. What is Spinal Muscular Atrophy (Werdnig-Hoffmann Disease).
How is it inherited?
What are 95% of cases due to?
What % of population carry mutation?
- Case 2
- Maggie - 13 months
- Respiratory difficulties, difficulty sucking and swallowing, ‘floppy’, unable to sit (usually do this 4-7 months)
- Diagnosed with Spinal Muscular Atrophy (Werdnig-Hoffmann Disease)
- It is progressive muscle weakness from degeneration of anterior horn cells
- Autosomal recessive inheritance for Werdnig-Hoffmann Disease
- 95% cases due to deletion of SMN1 (survival motor neurone 1)
- 1 in 50 population carry mutation
Case 2: Issues for family.
Where can there be risk of similar problems?
What is an option for further pregnancy?
- Case 2: Issues for family
- Not any real treatment options for Maggie, who will likely not live past the age of 2
- There is a risk of similar problem in a future pregnancy
- Options for further pregnancy
1) Prenatal diagnosis not an option
2) What about Pre-implantation genetic diagnosis?
* 1 cell is removed from a blastocyst at 5 days, and the genome can be amplified and analysed
* We can then identify the SMN1 mutations, and which parent they came from, then select embryos that do not carry these mutations for implantation
Case 3. What does early signs of pathologies on ultrasounds suggest?
- Case 3
- Ultrasound at 8 weeks – normal
- Ultrasound scan 13 weeks - Polycystic kidneys and Encephalocele
- At such an early stage – these pathologies suggest a poor prognosis
Case 3. What are 2 potential diagnoses for the pathologies present on ultrasound?
What could the couple potentially want to know?
- Case 3
- 2 potential diagnoses for the pathologies present on ultrasound:
1) Meckel Gruber syndrome
* Variable phenotype
* Autosomal recessive
* At least 6 genes
2) Trisomy 13 (Patau syndrome)
- The couple opted to abort and go for genetic counselling
- What the couple could potentially want to know:
1) What do these findings mean?
2) Could you have made a mistake
3) What do we do now?
4) What would you do?
Case 4. Family tree in photo
- Case 4.
- Jim - 53 years
- 3 year history of cognitive impairment
- 1 year history of personality change, loss of impulse control
- All investigations negative - diagnosis of Alzheimer’s disease made
- Brother and cousin also thought to be affected
- Blood sent to research lab in Belgium- mutation identified in PSEN-1 gene
- Referred to discuss family implications
- Family tree in photo
Case 4: Jim’s mutation. How can we get more clues?
- Case 4: Jim’s mutation
- Not in literature
- Not present in 119 early onset dementia patients from Scotland and Iceland
- Not present in 524 unaffected Scots
- Sequence highly conserved across species
- How can we get more clues?
- Look at other affected family members and see if they carry the same mutation
- Harry (Jim’s Brother): Terminally ill in Brisbane
- Alison (Jim’s sister): Residential care Quebec
- Family tree in photo
- What is the evidence of this?
- All affected individuals carry the mutation
- No evidence that it is found incidentally in Scottish population
- Wild type sequence conserved across species
- Sufficient evidence to offer pre-symptomatic testing
Case 4: Presymptomatic testing.
When can presymptomatic testing be done?
What are 3 parts of the pre-symptomatic testing protocol?
- Case 4: Presymptomatic testing
- Robert is Jim’s younger brother, and opted for pre-symptomatic testing
- Presymptomatic testing can be done when there is no preventative treatment available
- 3 parts of the pre-symptomatic testing protocol:
1) Full information on test and limitations
2) Non-directive
* Opportunity for facilitated decision making
3) Issues to consider
* Insurance
* Employment
* Relationships
