Genetics for GPR’s

1. Genetics for GPR’s Thank you for inviting me… Susan Fairgrieve Principal Genetic Counsellor

2. Aims • Highlight the relevance of genetics to your practice • Review skills in taking and interpreting family histories (discussing cases) • Making a referral

3. Recognition from RCGP Identifying patients Communicating genetic information Clinical management

4. What do you encounter?

5. Have you made a referral to Genetics? Do patients ask about either passing on or developing an illness that ‘runs in the family’? What proportion of the UK population will develop a genetic condition ? 1 in 20 before the age of 25, 60% in later life have conditions with a genetic component On average - how many consultations relating to family cancer do GPs have every year?

6. Common / Important Conditions Chromosomal disorders Syndromes: Down’s, Edward’s, Patau’s, Turner’s, Klinefelter’s. Chromosomal Translocations Autosomal recessive disorders Cystic Fibrosis Haemoglobinopathies Haemochromatosis Autosomal dominant disorders Familial Hypercholesterolemia Huntington’s Disease Marfan’s Syndrome Neurofibromatosis X-Linked disorders Duchenne Muscular Dystrophy Haemophilia A Fragile X syndrome Familial Cancer Bowel/Uterine/Ovarian ?HNPCC Breast/Ovarian/Prostate ?BRCA1/2 Variable inheritance patterns Deafness

7. Common Reasons for Referrals • Strong family history of breast/ovarian or bowel cancer (predictive genetic testing may sometimes be available) • Investigation, diagnosis and ongoing support for people with a genetic condition in the family • family history (e.g. Huntington’s Disease) • sporadic event (e.g. child with developmental delay) • Cascade testing where there is a known family history of a condition • Genetic counselling for prenatal diagnosis

8. The Appointment • The problem will be discussed in detail. • A family tree will be drawn • A medical examination may be carried out • The doctor or Genetic Counsellor will explain their findings and discuss all the options. • The patient will be encouraged to ask questions • Blood tests may be offered. • A plan may be made for further information gathering tests, or another appointment. • A letter is sent to the patient and GP

9. What does a genetics service offer? • Genetic Testing • Diagnosis • Genetic counselling • Patient information • Speciality services and clinics • Education and training • Telephone advice

10. Should I Refer? Couple in late 20s - she has 1 child by previous partner. No problems with conceiving or miscarriages with first partner Been together a few years and trying for family - 5 miscarriages around 10-12 week time Two ectopic pregnancies and now has no fallopian tubes

11. Options Draw family tree, include both partners ask about Miscarriages in other family members Individuals with learning difficulties Send bloods for Chromosomes Refer for Genetic Counselling

12. What happened? Bloods for Chromosomes sent • Female partner normal karyotype • Male partner’s report states that the quality of the sample was such that they could not exclude any subtle translocation

13. Reciprocal Translocation 7 7 10 10 7 10 der7 der10 7 10 der10 der7 10 der10 7 7 7 10 10 7 7 10 10 der7 Unbalanced Carrier Unbalanced Normal

14. Genetic Testing Diagnostic Carrier Prenatal Pre-implantation Genetic Diagnosis Predictive

15. Diagnostic Genetic Tests A diagnostic genetic test is performed to:- • Confirm a clinical diagnosis • IF a family history of cancer indicates a genetic predisposition to develop cancer Methods used • Cytogenetic to look at chromosomes • Molecular to look for gene alterations

16. 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

17. 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

18. Chorionic Villus Sample

19. Amniocentesis

20. 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 4 couples achieve a pregnancy

21. 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

22. Case study:Is my baby at risk of cystic fibrosis?

23. 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

24. / P X weeks Pedigree Symbols Male Marriage / Partnership (horizontal line) Female Partnership that has ended Person whose sex is unknown Offspring (vertical line) Pregnancy Miscarriage Parents and Siblings Affected Male & Female Carrier Male & Female

25. 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

26. Family History • Jane (28) is 6 weeks pregnant • Jane’s husband is Christopher (29) • This is their first baby

27. Christopher Hobson Jane 29 28 P 6 weeks

28. Family History • Christopher is an only child. • His father is William (60) • His mother is Margaret (59) • They are both alive and well

29. William Hobson Margaret 60 59 Christopher Hobson Jane 29 28 P 6 weeks

30. 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

31. Joan William Hobson Margaret George Whitehead 60 59 64 Died age 66 Christopher Hobson Jane John Whitehead 29 28 34 P 6 weeks

32. Family History • Jane’s brother John has one son David (10) to his first wife Alice (33). • Their marriage ended in divorce

33. Joan William Hobson Margaret George Whitehead 60 59 64 Died age 66 Christopher Hobson Jane Alice John Whitehead 29 28 33 34 P 6 weeks David 10

34. 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

35. Margaret Joan William Hobson George Whitehead 60 59 64 Died age 66 Christopher Hobson Jane Alice John Whitehead Christine 29 28 33 34 29 P 9 weeks 6 weeks David Richard 10 4 Cystic Fibrosis

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

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

38. Margaret George Whitehead William Hobson Joan 60 64 59 Died age 66 Christopher Hobson Jane Alice John Whitehead Christine 29 28 33 34 29 P 9 weeks 6 weeks David Richard 4 10 Cystic fibrosis or Is the probability of Jane Hobson being a carrier for Cystic Fibrosis sufficiently high to offer testing?

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

40. 1 1 1 100 25 4 Chance of passing on two copies of gene alteration for CF Jane’s risk of being a carrier Christopher’s risk of being a carrier Risk of baby being affected by CF = X X 1 = X X

41. Joan William Hobson Margaret George Whitehead 60 59 64 Died age 66 Christopher Hobson Jane Alice John Whitehead Christine 29 28 33 34 29 P 9 weeks 6 weeks David Richard 10 4 Cystic fibrosis When should specialist genetic advice be sought?

42. Joan William Hobson Margaret George Whitehead 60 59 64 Died age 66 Christopher Hobson Jane Alice John Whitehead Christine 29 28 33 34 29 P 9 weeks 6 weeks David Richard 10 4 Cystic fibrosis Which other family members should be offered carrier status testing?

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

44. 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

45. Alpha1 Antitrypsin Deficiency • MSZ Phenotype • SZ and ZZ • Advise re: smoking and alcohol • Check baseline lung function