1. Genetics in Primary Care Dr. Jude Hayward GPwSI in Genetics, Bradford

2. The Genetics Explosion 30 articles in the BMJ in the last 3 months 65 articles in the Guardian in the last 3 months Range of issues:  Genes for common diseases e.g. ‘The Fat Gene’  PIGD  GM crops  Forensic DNA database  HFEA bill – human / animal hybrids

3. What does Genetics mean to you? Tricky Dry Highly Specialised – sometimes the patients know more than you do Interesting challenge Hard to explain to patients

4. What does ‘genetics’ mean to you? Craniofaciocutaneous Syndrome Mental retardation ASD / HOCM Icthyosis Sparse Hair High Forehead Prominent ears Depressed nasal bridge

5. What would you like to know?

6. Family History – why do we do it? Think of the patient you most recently asked for a family history – what was the situation / presenting problem? What did you do with that information?

7. Family History – why do we do it? To aid with accurate risk assessment - likelihood of developing a certain disease To identify those who have an underlying genetic condition who would benefit from further information and services To identify other members of the family who may be at risk – affected / carrier This leads to appropriate management strategies

8. Objectives for today’s session To outline the scope of genetics in primary care To identify some useful guidelines and resources for clinicians To identify useful resources for patients To outline the structure of services providing care to patients with genetic issues To touch on common forms of inheritance To discuss some common presentations of patients with genetic issues To encourage ‘thinking Genetics’ where you might not have done before!

9. Scope of Genetics in Primary Care 10% of consultations have genetic aspect Mostly multifactorial disease with genetic component e.g. CHD, asthma, Alzheimers, diabetes Single gene disorders e.g. CF, Huntingdon’s, (Pharmacogenetics) Reproductive issues e.g. Hbopathies

10. Multifactorial Inheritance Increased risk due Genetic to family history Condition Environmental factorsGenetic Factors ‘nurture’ ‘nature’

11. Role of Primary Health Care Team (RCGP) General Practitioners have a key role in identifying patients and families who would benefit from being referred to appropriate specialist genetic services Management and support of families with / at risk of genetic conditions Consideration of FH in multi-factorial disease e.g. cancer, DM, CHD

12. A typical morning surgery…

13. A ‘typical’ morning surgery… Mrs. B, aged 52, attends for a blood pressure check as she has had 2 raised readings over the last few months. Today it is 152 / 96. She says she’s not surprised it is raised as she has just heard that her sister has been diagnosed with ovarian cancer – this has come as a shock as she has been supporting her other sister through a course of chemotherapy for breast cancer. What else would you ask?

14. Cancer is common 1 in 3 Of the general population will develop cancer during their lifetime Breast cancer: 1 in 9 women Ovarian cancer: 1 in 35 women Bowel cancer: 1 in 18 men, 1 in 20 women Incidence increases with age (risk factor)

15. Multifactorial Inheritance Increased risk due Genetic to family history Condition Environmental factorsGenetic Factors ‘nurture’ ‘nature’

16. Hereditary Cancer Syndromes 1 in 20 cases of breast, ovarian, CRC cancer are hereditary. Breast/ovarian cancer syndromes: BRCA 1 + 2  Ass. cancers: Male Breast Cancer, Prostate Cancer, Certain melanomas, association with CML / renal cell carcinoma Colorectal cancer syndromes: FAP / HNPCC  HNPCC associated cancers: ovarian, endometrial, gastric, biliary, urinary tract

17. Autosomal Dominant Inheritance

18. Risk assessment 40-50 patients age 35-64 per 2000 patients in GP have 1 first degree relative with CR, breast, ovarian or uterine cancer (UK) Familial Cancer: Primary Care Management of patients at risk of breast, ovarian or colorectal cancer Based on NICE and BSG guidelines OPERA – tool for patients via MacMillan website

20. Useful information to include in referral: Name, DOB, address, NHS number, (telephone number) Whatever family history available Pedigree number / Name(s) of affected family members if seen by any genetics team (Pregnant or non-pregnant)

21. Genetic Services Yorkshire Regional Genetic Service (based at LGI: switchboard 0113 243 2799)  Medical Staff: Consultants, Registrars  Genetic Counsellors  Family History Administrators  DNA / Cytology labs Other specialties: Paediatrics, Midwives Other services:  Haemoglobinopathy and Sickle Cell Service GPwSI in Genetics

22. What happens when a referral is made? Referral received (can be via secondary care) Questionnaire sent out by family history administrators and returned by pt Consultants review referral and FH Triage to Genetic Counsellor / Consultant

23. Genetic Counselling (Peter Rose) Information gathering:  Discuss family history  Identify patient concerns / wishes Information provision:  Explain risks and genetic contribution  Discuss screening if appropriate  Preventative measures  Discuss tests if appropriate Decision making:  Guide patient through difficult choices  Instigate management which patient chooses

24. Genetic Counselling IS NON-DIRECTIVE Doesn’t always result in a test! ‘ Genetic Counselling is the process by which patients or relatives at risk of a disorder which may be hereditary are advised of the consequences of the disorder, the probability of developing or transmitting it and the ways in which this may be prevented or avoided’

25. Familial / hereditary cancer Family History is used to assess risk Population risk:  should be reassured and managed in Primary Care Moderate / high risk (i.e. above population risk):  Additional screening (mammogram +/- MRI)  Risk-reducing surgery i.e. prophylactic mastectomy / oophorectomy High risk:  may be offered testing for a particular syndrome

26. ‘Typical’ patient no. 1 – Mrs. B Could / Should be offered referral to Genetics High risk for breast and ovarian cancer Offered screening:  Yearly Mammogram +/- MRI from 35-50  18 monthly mammogram from 50 onwards  Ovarian screening via research study Offered risk-reducing measures:  Prophylactic Bilateral Mastectomy  Prophylactic Bilateral Oophorectomy Offered testing:  Given information and testing discussed

27. A ‘typical’ morning surgery… Mrs T. attends, and after telling you about her athlete’s foot she bursts into tears and tells you her mother has just been diagnosed with cancer – ‘everyone in the family has it and I’m bound to get it’ What else do you ask? She tells you:  Mother had breast cancer aged 64  Sister had cervical cancer in her 30’s  Her grandfather had prostate cancer and died in his 80’s  Her uncle developed lung cancer in his 60’s – he had been a heavy smoker all his life

28. Role of Primary Care (NICE 2006) Women at or near population risk should be cared for in Primary Care They should receive standard information (see box in PACE Guidelines) ‘Be Breast Aware’ (NHS Breast Screening Programme and Cancer Research UK) ‘Are you worried about Breast Cancer?’ (www.macmillan.org.uk/cancerinformation)

29. Communication… How would you try to reassure her that she wasn’t at any greater risk than the rest of the population?

30. Aled

32. John

33. Other resources for patients www.macmillan.org.uk/cancerinformation 0808 808 0000 www.cancerhelp.org.uk www.cctrust.org.uk 020 7704 1137 http://www.macmillan.org.uk/Get_Support/ Cancer_types/Genetic_risk_factors.aspx http://www.macmillan.org.uk/Get_Support/ Cancer_types/Genetic_risk_factors.aspx Can access OPERA via macmillan website

34. The story so far… Our job is to identify the 1 in 20 patients with cancer (and their relatives) with a genetic basis (those in the red blob) PACE guidelines can help Only some patients will be offered a genetic test – management is mainly information giving, extra screening, risk- reducing surgery.

35. A typical morning surgery…

36. When to think about it: A 34-year-old lady with a history of depression comes to see you. Her sister died very suddenly 2 weeks ago at the age of 42. She also happens to be your patient, and when you look in her notes, the cause of death from PM is Myocardial Infarction

37. Familial Hypercholesterolaemia 1 in 500 people have Familial Hypercholesterolaemia 50% CVD risk by the age of 50 in men 30% CVD risk by the age of 60 in women 110,000 cases in the U.K. Only around 10,000 identified so far

38. Hot Topic at present… NICE guidelines: Familial Hypercholesterolaemia (August 2008)

39. When to think about it: Simon Broome Diagnostic Criteria TC >7.5, LDL >4.9 AND Definite FH:  Tendon xanthomas in 1 st or 2 nd degree relative Possible FH:  Family history of IHD <60 y.o.a. in 1st degree relative, and <50 y.o.a. in 2 nd degree relative  Family history of TC >7.5 in 1 st or 2 nd degree relative

40. Fig. Disease box 11 ©Scion Publishing Ltd Photos courtesy of Dr Paul Durrington. Cholesterol deposition in patients heterozygous for familial hypercholesterolemia. (a, b) Tendon xanthomata, and (c) corneal arcus.

41. DO NOT USE THESE!

42. How to manage it: Manage other risk factors Aggressively control cholesterol to lower LDL <50% level at initial measurement If not controlled with 2 agents, refer:  Donald Whitelaw (Diabetes and Endocrinology Consultant, BRI)  Julian Barth / Mike Mansfield (Lipid clinic, LGI) Assess for symptoms of IHD

43. What about the Genetics? Autosomal Dominantly Inherited Mutation in LDL receptor gene Individuals should be referred for genotyping and cascade screening Resources and Services in response to NICE……………provision variable, and cascade screening often not in place

44. What about the rest of the family? ‘Cascade Screening’ of all 1 st and 2 nd degree relatives – several pilot projects underway to figure out how to do this. Controversies:  How do you assess for possible IHD?  Children should be started on a statin as early as possible, around the age of 10

45. The story so far… If someone has a family history of premature heart disease or presents with a cholesterol over 7.5: Think Familial Hypercholesterolaemia

46. Other inherited cardiac conditions Specialist clinic at LGI FH of sudden cardiac death FH of arrythmia, cardiomyopathy or connective tissue disease Can refer directly Any queries: Kath Ashcroft  0113 3925784 or mobile 07789003997

47. A typical morning surgery…

48. A ‘typical’ morning surgery… A 36-year-old man comes in ‘tired all the time’. He has several non-specific symptoms including palpitations and general aches, and you are aware he is having a stressful time at work. He is concerned, and asks you to do some blood tests.

49. Hereditary haemochromatosis High index of suspicion in younger men who present TATT. Autosomal recessive disorders, carrier rate 1/8 – 1/10, prevalence 1/200 – 1/400. Signs, Symptoms and Complications:  Non-specific – tatt, joint pain, weight loss, (impotence)  Liver disease  Diabetes  Hypogonadotrophic hypognadism  Arthritis  Cardiac Disease (heart failure) Venesection improves life expectancy - normal if before development of diabetes and liver cirrhosis

50. Hereditary haemochromatosis His ferritin came back as 458. What would you do next? Diagnosis:  Ferritin: will be raised once iron overload occurring. Can also be raised in acute phase response  If ferritin high, or high index of suspicion consider checking Fasting Transferrin (earliest marker of HH)  If transferrin > 45%, refer to haematologist  Generally, females >50%, males >55%

51. Hereditary Haemochromatosis Genetics:  2 mutations responsible for >95% in U.K.  Many people who inherit the mutations will not develop clinical disease.  Genetics dept will offer gene testing / genotyping to 1st degree relatives only.

52. Other examples! A 24-year-old man who is diagnosed with Type 2 Diabetes. He has a normal BMI, is caucasian, and has no family history. A 59-year-old man who is caring for his wife who has just been diagnosed at 57 with early onset Alzheimer’s. Her mother also had dementia of some sort.

53. A typical morning surgery…

54. Offspring Sperm & eggs AffectedCarrier Parents Carrier Normal Recessive Inheritance

55. Autosomal Recessive Inheritance –Affects one generation –Both sexes affected –Male – male transmission

56. National Screening Committee Timeline

57. Other conditions… Any children elsewhere in the family with difficulties? For instance hearing or visual impairment? Problems at school, or have regular out- patient appointments? Recurrent miscarriage or stillbirth.

58. Resources for patients www.cafamily.org.uk  Support for families in which there is a rare genetic disorder

59. This is the slide to remember! Our role is identify patients at risk or who may have a genetic condition and would benefit from input from Genetic Services We do this by taking and using a family history – core examples:  A common multifactorial disease (e.g. IHD or cancer) occurring young, strong family history, atypical presentation  Early pregnancy, or even pre-conceptually There is lots of information out there regarding individual conditions

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

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

62. Resources: Me! judith.hayward@bradford.nhs.ukjudith.hayward@bradford.nhs.uk YGS via LGI switchboard: 0113 243 2799 www.gpnotebook.com www.geneticseducation.nhs.uk ‘Recognising the common patterns of inheritance in families’ www.library.nhs.uk/genepool www.chime.ucl.ac.uk (apogi sheets www.chime.ucl.ac.uk

63. Thank you! Any questions?

64. 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

65. Family History Jane (28) is 6 weeks pregnant Jane’s husband Christopher (29) is an only child His parents William (60) and Margaret (59) are alive and well Jane has one brother John (34), he had one son David (10) to his first wife Alice (33). Their marriage ended in divorce John’s second wife Christine (29) had a miscarriage at 9 weeks and a son Richard (4) who has CF Jane’s father George Whitehead died at the age of 66 Jane’s mother Joan (64) is alive and well Supporting Genetics Education for Health www.geneticseducation.nhs.uk

66. 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