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. The Daily Telegraph Genetic breakthrough hails new cancer research era
From The Times
September 7, 2009
Genetic breakthrough brings cure for Alzheimer’s a step closer                                 
December 16th 2009
Genetic breakthrough hails new cancer research era
By Richard Alleyne, Science Correspondent
The genetic code of two of the most deadly cancers has been cracked by British scientists in a world first that opens up a whole new era in the treatment for the disease.
(Science Photo Library)
Inflammation seen in the brains of Alzheimer's sufferers was thought to be a secondary effect of the disease. The new findings suggest that it might actually be a primary cause
David Rose, Health Correspondent
Supporting Genetics Education for Health

4. 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

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

6. What would you like to know?

7. 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?

8. 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
This leads to appropriate management strategies

9. 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!

10. 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

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

12. 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

13. A typical morning surgery…

14. 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?

15. Of the general population will develop cancer during their lifetime
Cancer is common
1 in 3-4
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)

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

17. Recognising Hereditary/Familial Ca
Younger age at diagnosis of cancer
Multiple family members affected
Same cancers
Bilateral, or multiple primaries
Related cancers.... (unusual cancers)

18. Hereditary Cancer
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

19. Autosomal Dominant Inheritance

20. Risk assessment
40-50 patients age 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

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

23. Genetic Services
Yorkshire Regional Genetic Service (based at LGI: switchboard )
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

24. 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
Often initial contact with Genetic Counsellor

25. 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
Institute management which patient chooses

26. 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’

27. 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

28. ‘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

29. 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

30. 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?’ (Cancer Backup)

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

32. Aled

34. John

35. Other resources for patients
Can access via macmillan website

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

37. A typical morning surgery…

38. 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

39. 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

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

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

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

43. DO NOT USE THESE!

44. 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)
Consider referral to cardiologist for assessment of possible IHD

45. What about the Genetics?
Autosomal Dominantly Inherited
Mutation in LDL receptor gene
Individuals should be referred for genotyping.

46. What about the rest of the family?
‘Cascade Screening’ of all 1st and 2nd 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

47. 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

48. 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
or mobile

49. A typical morning surgery…

50. 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.

51. 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

52. Hereditary haemochromatosis
His ferritin came back as 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%

53. 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.

54. 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.

55. A typical morning surgery…

56. Recessive Inheritance
Parents
Carrier
Sperm & eggs
With all recessive conditions, the child can only be affected if both parents are carriers. However, rarely new mutations can and do occur
The slide is sequenced, at each level explain:
Both parents are carriers: they each have one altered and one usual copy of the gene instead of two usual copies. Carriers are usually healthy
Each sperm and egg cell (gamete) has a 50% chance of containing the altered copy of the gene, or a 50% chance of containing the usual gene
If both parents are carriers, AT CONCEPTION each child has a 25% (1 in 4) risk of being affected with the condition and a 50% (1 in 2) chance of being a carrier
Offspring
Normal
Carrier
Carrier
Affected

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

58. Resources for patients
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

61. Supporting Genetics Education for Health
An on-line resource to support the genetics curriculum statement is the ‘genetics in primary care module’ of the eGP project.
Supporting Genetics Education for Health 61

62. Resources: Me! judith.hayward@bradford.nhs.uk
YGS via LGI switchboard:
‘Recognising the common patterns of inheritance in families’
(apogi sheets

63. Thank you!
Any questions?

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

65. Supporting Genetics Education for Health
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

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