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

Genetics in Primary Care

Dr. Jude Hayward

GPwSI in Genetics, Bradford

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

Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk

From The TimesSeptember 7, 2009

Genetic breakthrough brings cure for Alzheimer’s a step closer

(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 causeDavid Rose, Health Correspondent

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.

December 16th 2009

The Daily Telegraph

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

What does ‘genetics’ mean to you?

Craniofaciocutaneous Syndrome

Mental retardationASD / HOCM

IcthyosisSparse Hair

High ForeheadProminent ears

Depressed nasal bridge

What would you like to know?

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?

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

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!

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

Multifactorial Inheritance

Increased risk due Genetic to family history Condition

Environmental factors Genetic Factors‘nurture’ ‘nature’

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

A typical morning surgery…

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?

Cancer is common

1 in 3-4Of 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)

Multifactorial Inheritance

Increased risk due Genetic to family history Condition

Environmental factors Genetic Factors‘nurture’ ‘nature’

Recognising Hereditary/Familial Ca

Younger age at diagnosis of cancer Multiple family members affected Same cancers Bilateral, or multiple primaries Related cancers.... (unusual cancers)

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

Autosomal Dominant Inheritance

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

www.learnonline.nhs.uk Based on NICE and BSG guidelines

OPERA – tool for patients via MacMillan website

http://www.learnonline.nhs.uk/

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)

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

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

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

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’

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

‘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


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

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)

Communication…

How would you try to reassure her that she wasn’t at any greater risk than the rest of

the population?

Aled

Maud

CRC@58

Sian

CRC@57

Aled

37

Olwen

34

Huw

CRC@54

Dai

34

Wynn

33

Browyn

50

Tom

29

John

Died young?renal Ca

MargaretRenal Ca@42

RoyRenal Ca@50

Pat58

Jenny40

John38

Richard35

Mark33

Judith30 28

Jane20

Julian18

Becky16

Lily13

Other resources for patients

www.cancerbackup.org.uk 0808 800 1234 www.cctrust.org.uk 020 7704 1137 http://www.macmillan.org.uk/Get_Support/

Cancer_types/Genetic_risk_factors.aspx Can access via macmillan website

http://www.cancerbackup.org.uk/

http://www.cctrust.org.uk/

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

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.


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

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

Hot Topic at present…

NICE guidelines:

Familial Hypercholesterolaemia

(August 2008)

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

Fig. Disease box 11 ©Scion

Publishing LtdPhotos courtesy of Dr Paul Durrington.

Cholesterol deposition in patients heterozygous for familial hypercholesterolemia. (a, b) Tendon xanthomata, and (c) corneal arcus.

DO NOT USE THESE!

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

What about the Genetics?

Autosomal Dominantly Inherited Mutation in LDL receptor gene Individuals should be referred for

genotyping.

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

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

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



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.

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

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%

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.

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.


Offspring

Sperm & eggs

AffectedCarrier

Parents

CarrierCarrier

CarrierNormal

Recessive Inheritance

Autosomal Recessive Inheritance

– Affects one generation– Both sexes affected– Male – male

transmission

Resources for patients

www.cafamily.org.ukSupport for families in which there is a rare

genetic disorder

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



Resources:

Me! [email protected] 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

Thank you!

Any questions?


Male

Female

Person whose sex is unknown

PregnancyP

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


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



JoanMargaret

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 WhiteheadDied age 66

Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic fibrosis

9 weeks

Christopher Hobson29

William Hobson60 59

P

6 weeks

Alice33

David10

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

Documents

nature slide

chd slide

hbopathies slide

bradford slide

hereditary cancer

prostate cancer

crc cancer

women ovarian cancer