1. Supporting Genetics Education for Health www.geneticseducation.nhs.uk NHS National Genetics Education and Development Centre Genetics for GPs Thank you for inviting me… Susan Fairgrieve, GEF (Genetics Education Facilitator) for the NE region

2. Genetic Testing Diagnostic Carrier Prenatal Pre-implantation Genetic Diagnosis Predictive Supporting Genetics Education for Health www.geneticseducation.nhs.uk

3. Diagnostic Tests A diagnostic test is performed to:- Confirm a clinical diagnosis Family history of cancer Methods used Cytogenetic to look at chromosomes Molecular to look for gene alterations Supporting Genetics Education for Health www.geneticseducation.nhs.uk

4. Carrier Test When there is a known genetic condition in the family and other family members are at risk of being a carrier. Being a carrier does not have any implications for their own health but may have implications for future pregnancies. Examples –Cystic Fibrosis –Chromosomal translocation Supporting Genetics Education for Health www.geneticseducation.nhs.uk

5. Prenatal Test Prenatal tests are available if: –known familial genetic mutation –known chromosomal abnormality –high risk identified by a screening programme Prenatal tests are invasive –Chorionic Villus sample performed from 11 weeks –Amniocentesis performed from 15 weeks Supporting Genetics Education for Health www.geneticseducation.nhs.uk

6. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Chorionic Villus Sample

7. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Amniocentesis

8. Pre Implantation Genetic Diagnosis Available for limited number of conditions Assisted conception Analysis of a single cell from 8 cell embryo Up to 2 unaffected embryos transferred Approx 1 in 5 couples achieve a pregnancy

9. Predictive Test In dominant genetic conditions, if the individual inherits the gene alteration they will: – develop the condition at a later stage, e.g. Huntington’s Disease –be at increased risk of developing a cancer in families with a family history and a known gene alteration Supporting Genetics Education for Health www.geneticseducation.nhs.uk

10. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Case study: Is my baby at risk of cystic fibrosis?

11. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Jane Hobson is in the early stages of pregnancy and is consulting you about the risks to her baby of having cystic fibrosis. Her nephew Richard Whitehead was diagnosed as having cystic fibrosis as a result of the neonatal screening programme. Drawing a pedigree

12. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Male Female Person whose sex is unknown Pregnancy P Marriage / Partnership (horizontal line) Parents and Siblings Offspring (vertical line) Affected Male & Female Carrier Male & Female Partnership that has ended Pedigree Symbols / X weeks Miscarriage Supporting Genetics Education for Health www.geneticseducation.nhs.uk

13. Practicalities Start in the middle of the page Use the standard symbols Be systematic with questions Try to find out about three generations Ask sensitively about: –Children from other relationships –Miscarriages and stillbirths –Disabilities and serious illnesses –Consanguinity –Causes of death, particularly premature Supporting Genetics Education for Health www.geneticseducation.nhs.uk

14. Family History Jane (28) is 6 weeks pregnant Jane’s husband is Christopher (29) This is their first baby Supporting Genetics Education for Health www.geneticseducation.nhs.uk

15. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Jane 28 Christopher Hobson 29 P 6 weeks

16. Family History Christopher is an only child. His father is William (60) His mother is Margaret (59) They are both alive and well Supporting Genetics Education for Health www.geneticseducation.nhs.uk

17. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Jane 28 Christopher Hobson 29 William Hobson 60 Margaret 59 P 6 weeks

18. Family History Jane has one brother John (34) Jane and John’s father George Whitehead died at the age of 66 Jane and John’s mother Joan (64) is alive and well Supporting Genetics Education for Health www.geneticseducation.nhs.uk

19. Supporting Genetics Education for Health www.geneticseducation.nhs.uk George Whitehead Died age 66 Joan 64 John Whitehead 34 Jane 28 Christopher Hobson 29 William Hobson 60 Margaret 59 P 6 weeks

20. Family History Jane’s brother John has one son David (10) to his first wife Alice (33). Their marriage ended in divorce Supporting Genetics Education for Health www.geneticseducation.nhs.uk

21. Supporting Genetics Education for Health www.geneticseducation.nhs.uk George Whitehead Died age 66 Joan 64 John Whitehead 34 Jane 28 Christopher Hobson 29 William Hobson 60 Margaret 59 P 6 weeks Alice 33 David 10

22. Family History John’s second wife is Christine (29) Christine had a miscarriage at 9 weeks They then had a son Richard (4) who has cystic fibrosis Supporting Genetics Education for Health www.geneticseducation.nhs.uk

23. Supporting Genetics Education for Health www.geneticseducation.nhs.uk George Whitehead Died age 66 Joan 64 John Whitehead 34 Jane 28 Christine 29 Richard 4 Cystic Fibrosis 9 weeks Christopher Hobson 29 William Hobson 60 Margaret 59 P 6 weeks Alice 33 David 10

24. Supporting Genetics Education for Health www.geneticseducation.nhs.uk From the family pattern, who must be carriers for cystic fibrosis? Margaret George Whitehead Died age 66 Joan 64 John Whitehead 34 Jane 28 Christine 29 Richard 4 Cystic fibrosis 9 weeks Christopher Hobson 29 William Hobson 60 59 P 6 weeks Alice 33 David 10

25. Supporting Genetics Education for Health www.geneticseducation.nhs.uk

26. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Is the probability of Jane Hobson being a carrier for cystic fibrosis sufficiently high to offer testing? or Supporting Genetics Education for Health www.geneticseducation.nhs.uk George Whitehead Died age 66 Joan 64 John Whitehead 34 Jane 28 Christine 29 Richard 4 Cystic fibrosis 9 weeks Christopher Hobson 29 William Hobson 60 Margaret 59 P 6 weeks Alice 33 David 10

27. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Joan Margaret Assume Jane was tested and found to be a carrier. What is the probability that the baby in Jane and Christopher Hobson’s current pregnancy will have cystic fibrosis? (Population risk of being CF carrier for people with North European ancestry = 1 in 25) George Whitehead Died age 66 Joan 64 John Whitehead 34 Jane 28 Christine 29 Richard 4 Cystic fibrosis 9 weeks Christopher Hobson 29 William Hobson 6059 P 6 weeks Alice 33 David 10

28. Jane’s risk of being a carrier Christopher’s risk of being a carrier Risk of baby being affected by CF 1 1 4 Chance of passing on two copies of gene change for CF 1 100 1 25 X X X X = = Supporting Genetics Education for Health www.geneticseducation.nhs.uk

29. Supporting Genetics Education for Health www.geneticseducation.nhs.uk Joan Margaret When should Genetic advice be sought? George Whitehead Died age 66 Joan 64 John Whitehead 34 Jane 28 Christine 29 Richard 4 Cystic fibrosis 9 weeks Christopher Hobson 29 William Hobson 6059 P 6 weeks Alice 33 David 10 Which other family members should be offered carrier status testing?

30. Congenital hypothyroidism PKU Newborn Bloodspot Cards Congenital hypothyroidism PKU MCADD Cystic Fibrosis Sickle Cell Disease & Beta thalassaemia major Newborn Screening

31. Down’s Syndrome Screening Combined Test 11 - 13 +6 weeks: - Nuchal Translucency - Serum PAPPA and Free βhCG Serum Screening 15 – 20 weeks: - AFP, βhCG, Oestriol, Inhibin A Supporting Genetics Education for Health www.geneticseducation.nhs.uk

32. Down’s Syndrome 95% Regular Trisomy 4% Translocation 1% Mosaic Supporting Genetics Education for Health www.geneticseducation.nhs.uk

33. NormalCarrierTrisomy 14Trisomy 21 Robertsonian Translocation

34. Daughter Son Parents Gametes At conception X-LINKED INHERITANCE WHERE THE MOTHER IS A CARRIER FatherMother XYXX (Carrier) (Affected) (Carrier) (Unaffected)

35. Fragile X Syndrome Supporting Genetics Education for Health www.geneticseducation.nhs.uk Fragile X Syndrome is the most common identifiable cause of inherited intellectual disability (mental handicap). It can cause a wide range of difficulties with learning, as well as social, language, attentional, emotional and behavioural problems.

36. Duchenne Muscular Dystrophy Supporting Genetics Education for Health www.geneticseducation.nhs.uk Fig. 1.4 ©Scion Publishing Ltd Histology photos courtesy of Dr Richard Charlton. (a) Affected boys stand up by bracing their arms against their legs (Gower’s manoeuvre) because their proximal (eg muscles are weak. (b) and (c) Muscle histology (Gomori trichrome stain). Normal muscle (b) shows a regular architecture of cells with dystrophin (brown stain) on all the outer membranes. (c) Shows muscle from a 10-year-old affected boy. Note the disorganisation, invasion by fibrous tissue and complete absence of dystrophin. Histology photos courtesy of Dr Richard Charlton, Newcastle upon Tyne.

37. Supporting Genetics Education for Health www.geneticseducation.nhs.uk

38. Reciprocal Translocation Normal Carrier Unbalanced 7710 7der7der10 7710 7der7der10 7 der7 10 7 7 der10

39. Ethical Issues 1 Mr P was recently diagnosed with ADPKD. Having realised each of his children has a 50% chance of having inherited the condition from him, Mr P asks the GP to organise a kidney ultrasound for his two children aged 10 and 7, to see if they have inherited the condition. The GP should do so. Consider the statement above to what extent do you agree or disagree with it? Supporting Genetics Education for Health www.geneticseducation.nhs.uk

40. Ethical Issues 2 Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disorder affecting ~ 1 in 3000 male births. Boys with DMD are diagnosed between 4-5 years In about 2/3 cases, the mother is a carrier. No treatment Neonatal screening of all male births should be performed to identify affected boys so their mothers can be tested to see if they are carriers and so at risk of having further affected pregnancies Supporting Genetics Education for Health www.geneticseducation.nhs.uk

41. Making a referral Draw a family pedigree Patient’s date of birth, address, telephone number, GP, NHS Number Affected / carrier person’s name, Date of Birth, genetic condition, relationship to patient Details of anyone already known to genetics

42. Taking a sample Ensure the patient is aware of the possible implications of the result for themselves and other family members before the blood sample is taken. Obtain consent for the procedure, document whether the patient is happy for results to be shared with other relevant health professionals and family members. Arrange how, when and from whom the patient will receive the results.

43. Sending a blood sample to Genetics 1 Single gene disorder 5ml venous blood sample in an EDTA tube Clearly label blood tubes with 3 reference points, name, date of birth and NHS number On a form need the same details + – details of the test required – details of affected/carrier family members – Clearly mark as Urgent with weeks gestation – Telephone contact of person giving result

44. Sending a blood sample to Genetics 2 For Autosomal Recessive conditions such as Cystic Fibrosis, Tay Sachs, send a sample from both partners Send each partner on a separate form with linking identifiers

45. Sending a blood sample to Genetics 3 Chromosome Disorders: 5ml venous blood sample in a Lithium Heparin tube Details as before

46. Case Studies Supporting Genetics Education for Health www.geneticseducation.nhs.uk

47. Case Study Young lady asks about her risk of developing Alpha 1 Antitrypsin Deficiency Her father has recently been diagnosed How would you explain her risk? What tests would you consider? Supporting Genetics Education for Health www.geneticseducation.nhs.uk

48. Alpha1 Antitrypsin Deficiency Phenotype M,S and Z variants of the AAT gene SZ and ZZ produce reduced amounts of Alpha 1 antitrypsin. –Advise re: smoking and alcohol intake –Check baseline lung function – Refer to respiratory physician –Refer to genetics to discuss cascade testing for partner and siblings Supporting Genetics Education for Health www.geneticseducation.nhs.uk

49. Case Study 36 year old male patient presents with feeling tired all the time. He has several non-specific symptoms including palpitations and general aches. You are aware he is having a stressful time at work. Supporting Genetics Education for Health www.geneticseducation.nhs.uk What testing would you consider?

50. Haemochromatosis AR, common mutations C282Y and H63D If C282Y/C282Y or C282Y/H63D 1-3 yearly screening –fasting transferrin saturation and serum ferritin Refer if –>50% transferrin saturation –>300mcg/l ferritin in men and post menopausal women –>200 mcg/l in premenopausal women Supporting Genetics Education for Health www.geneticseducation.nhs.uk