Genetics in Primary Care Dr. Jude Hayward GPwSI in Genetics, YRGS Dr. Brooke & Ptrs, Bradford.

Genetics in Primary Care

Dr. Jude Hayward

GPwSI in Genetics, YRGS

Dr. Brooke & Ptrs, Bradford.

The Genetics Explosion:‘Cancer: 'How I beat my DNA timebomb’’

‘'Designer baby' to be free from breast cancer:A British woman has made history by conceiving the country's first "designer baby" guaranteed to be free from hereditary breast cancer.’

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are needed to see this picture.

‘New DNA profiling technology could tell police who suspects are in under an hour:

A new portable device that can identify suspects in less than an hour using DNA left at the scene of a crime is set to transform the way police track down criminals.’

‘GM food needed to avert global crisis, says Government adviser’

What does Genetics mean to you?

Tricky Dry Highly Specialised – sometimes the patients

know more than you do Interesting challenge Difficult to explain to patients The murky quagmire you don’t want to enter….

What does ‘genetics’ mean to you?

Craniofaciocutaneous Syndrome

Mental retardationASD / HOCM

IcthyosisSparse Hair

High ForeheadProminent ears

Depressed nasal bridge

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

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

Communication of Genetic Information

What would you like to know?

Objectives for today’s session

Through discussion of cases:To outline the scope of genetic issues in primary careTo discuss some common presentations of patients with genetic issuesTo identify some useful guidelines and resources for cliniciansTo identify useful resources for patientsTo touch on basic genetics / inheritance patternsTo outline the structure of services providing care to patients with genetic issuesTo 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, Alzheimer's, diabetes

Single gene disorders e.g. CF, Huntingdon’s, Reproductive issues e.g. Hbopathies (Genomic Medicine) (Pharmacogenetics)

Multifactorial Inheritance

Increased risk Autosomally on basis of inherited /

Family History Single/gene Condition

Environmental factors Genetic Factors‘nurture’ ‘nature’

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 8 women Ovarian cancer: 1 in 50 women Bowel cancer: 1 in 18 men, 1 in 20 women Incidence increases with age (risk factor)

Multifactorial Inheritance

Increased risk Autosomally on basis of inherited /

Family History Single/gene Condition

Environmental factors Genetic Factors‘nurture’ ‘nature’

Hereditary Cancer Syndromes

1 in 20 cases of breast, ovarian, CRC cancer are the result of an underlying hereditary cancer syndrome.

Breast/ovarian cancer syndromes: BRCA 1 + 2 Breast (80% lifetime risk), Ovarian (40% lifetime risk) Ass. cancers: Male Breast Cancer, Prostate Cancer, Certain melanomas, association with

CML / renal cell carcinoma

Colorectal cancer syndromes: FAP / HNPCC CRC: FAP (100% lifetime risk) HNPCC (80% risk in males) HNPCC associated cancers: ovarian, endometrial, gastric, biliary, urinary tract

Autosomal Dominant Inheritance

Autosomal Dominant Inheritance

Family history…

Who affected (maternal and paternal sides) How many relatives affected Cancer type Age at diagnosis Other risk factors (e.g. smoking)

She tells you that her: Sister: breast cancer aged 52 Sister: ovarian cancer aged 48 Father’s sister: breast cancer aged 61

Risk assessment

Familial Cancer: Primary Care Management of patients at risk of breast, ovarian or colorectal cancer (Watch this Space!!)

Based on NICE and BSG guidelines

OPERA – tool for patients via MacMillan website

The future! User-friendly family history tool linked to risk calculator in Primary Care

Systems Use of google health - on-line family history questionnaires which can

be accessed by health care professionals

Useful information to include in referral: Usual personal details Whatever family history available Pedigree number / Name(s) of affected

family members if seen by any genetics team

(Pregnant or non-pregnant)

Genetic Services

Yorkshire Regional Genetic Service - very accessible!

(based at CAH: switchboard 0113 243 2799) Covers Yorkshire and Humberside

Medical Staff: Consultants, Registrars, GPwSI Counselling and diagnostic role Sub-specialise Cancer Genetics Team: Geneticist, Oncologist, GPwSI

Genetic Counsellors - counselling role Family History Administrators - collate info DNA / Cytology labs - testing and research

What happens when a referral is made?

Referral received (can be via secondary care)

Questionnaire

Information collated by Family History Administrators

Consultants/ GPwSI review Questionnaire

Triage to Genetic Counsellor / Consultant / GPwSI

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 and NON-JUDGEMENTAL 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

Population risk: should be reassured

and managed in Primary Care

Moderate risk (i.e. above population risk): Can be managed in

secondary care Additional screening

(annual mammogram from 40)

NBSP

‘Typical’ patient no. 1 – Mrs. B

High risk for breast and ovarian cancer Offered screening:

Additional mammograms from age 40 MRI if mutation carrier or at 50% risk Ovarian screening likely to be proven ineffective

Offered risk-reducing measures: Prophylactic Bilateral Mastectomy Prophylactic Bilateral Oophorectomy

Offered testing: Given information and testing of affected relative discussed

Prophylactic Tamoxifen…

To test or not to test…

Can inform risk Can reduce uncertainty May reassure May indicate if at risk of linked

cancers - improve vigilance May alter access to screening Can be used as a decision aid

re prophylactic surgery Can allow access to testing for

unaffected family members – PREDICTIVE TESTING

Cannot always give definitive result

Cannot predict whether someone will or won’t get cancer

Cannot predict when or how cancer may present

Psychosocial consequences May not be needed to access

screening / surgery May have implications for

insurance applications


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 Paternal 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?’ (www.macmillan.org.uk/cancerinformation)

Communication…

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

the population?

Contraceptive / HRT issues

COCP: breast ca risk similar in those with or without family history (NICE, UKMEC 1)

Reduced ovarian ca risk but not an indication BRCA1 mutation: 20% risk in ever use of COCP Preferable to use non-hormonal methods, or PO

with lowest systemic dose (i.e POP/IUS) HRT: breast ca risk similar in those with or

without family history (Million Women Study)

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.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 Can access OPERA via macmillan website

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 (those in the red blob)

PACE guidelines can help Genetic testing is only one aspect of

management – also comprises information giving, extra screening, risk-reducing surgery.

Miss T:

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

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.

How to manage it:

Manage other risk factors Aggressively control cholesterol to lower LDL

<50% level at initial measurement (treatment algorithm in NICE guidelines)

If not controlled with 2 agents, refer: Donald Whitelaw (Diabetes Consultant, BRI) Andy Pettit (Diabetes Consultant, AGH) Julian Barth / Mike Mansfield (Lipid clinic, LGI)

Assess for symptoms of IHD

What about the Genetics?

Autosomal Dominant Mutation in LDL receptor gene Cascade screening. Genotyping not widely available Role of primary care?

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.

Mr. S, patient no 4.

A 46-year-old gentleman comes in, and places a report in front of you. It lists his lifetime risk of many common conditions, but he is particularly concerned about his 45% lifetime risk of atrial fibrillation.

Genomics

Testing the ‘whole’ genome Population-based studies identify variants which have

increased frequency in individuals who have a particular condition

No assumption re mode of inheritance No prior knowledge of molecular mechanism needed Detect genetic mutation with small effect Research: map loci / possible mechanisms

Susceptibility loci

The position of these variants is then mapped to a particular locus – ‘susceptibility loci’

Increase likelihood of developing a particular condition

But aren’t necessary or sufficient

Personalised medicine?

Limited applications – but its coming! Pharmacogenetics (azathioprine) Tumour profiling (Herceptin) Potentially used to increase risk

stratification e.g. breast / prostate ca screening

Phenotypic data still better predictors

How would you manage Mr. S?

Manage risk factors Manage concerns ELSI implications Genetic fatalism or change in behaviour?

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.

Time for tea!

Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk

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

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

www.geneticseducation.nhs.uk

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

Resources for patients

www.geneticalliance.org.uk

SWANUK

[email protected]

www.cafamily.org.uk

Support for families in which there is a rare genetic disorder

Thank you!

Any questions?

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




Joan64

John Whitehead34

Jane28


William Hobson60

Margaret59

P

6 weeks

Family History

Jane’s brother John has one son David (10) to his first wife Alice (33).

Their marriage ended in divorce




Joan64

John Whitehead34

Jane28


William Hobson60

Margaret59

P

6 weeks

Alice33

David10

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




Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic Fibrosis

9 weeks


William Hobson60

Margaret59

P

6 weeks

Alice33

David10


From the family pattern, who must be carriers for cystic fibrosis?

Margaret George WhiteheadDied age 66

Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic fibrosis

9 weeks


William Hobson60 59

P

6 weeks

Alice33

David10


Is the probability of Jane Hobson being a carrier for cystic fibrosis sufficiently high to offer testing?

or


George Whitehead Died age 66

Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic fibrosis

9 weeks


William Hobson60

Margaret59

P

6 weeks

Alice 33

David10


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)


Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic fibrosis

9 weeks


William Hobson60 59

P

6 weeks

Alice33

David10

Jane’s risk of being a

carrier

Christopher’s risk of being

a carrier

Risk of baby being affected

by CF

11

4

Chance of passing on two copies of gene change for CF

1

100

1

25

XX

X X =

=



JoanMargaret

When should Genetic advice be sought?


Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic fibrosis

9 weeks


William Hobson60 59

P

6 weeks

Alice33

David10

Which other family members should be offered carrier status testing?

Consanguineous Marriage

What is Consanguinity

WHO defines consanguineous marriage as one between individuals who are second cousins or more closely related.

Consanguinity comes from the Latin words: con meaning shared and sanguis meaning blood.

The global distribution of consanguineous marriage

History of Consanguineous Marriage in Europe

Consanguineous marriage was prevalent until the 20th century, and was associated with royalty and land-owning families

Brain Storm!

What are the perceived benefits and disadvantages of cousin marriages?

Perceived benefits of cousin marriages Keeping property and money within a

family Staying within a well understood family

unit Improving the position of women by

reducing the chances of mistreatment from a husband bound by family ties.

Perceived Disadvantages of cousin marriages Risk of genetic conditions in offspring Anxiety about social stigma Difficulty living an autonomous married life

separate from the wider family

Why is there an offspring risk associated with consanguinity? When gametes formed, a few alterations in the DNA code will

occur – usually result in healthy carrier state. Only when two people who carry the same alteration / mutation

reproduce is there an increased chance of autosomal recessive disease

This occurs in conditions with a higher carrier rate in the general population, people of similar ethnicity, and people who are related

A related couple are more likely to have an alteration in the same gene because they have both inherited some of their genes from their shared relatives. In the case of first cousins, both of them could have inherited the same changed gene from one of the grandparents that they share.

Consanguineous couples are therefore at increased risk of having a child with an autosomal recessive condition.

Autosomal Recessive Inheritance

Risk Of Having a Child with Severe Congenital or Genetic Disorder Diagnosed by 1 yr of Age

Unrelated parents 2-3%First cousins 4-5%Second cousin 3-4%Double first cousins 6-7%BUT also increased with maternal age,

smoking, drinking, drugs, poor nutrition, poor obstetric/healthcare

Risk of having a child with disability

Risk for first cousins is still low (i.e. 4% instead of 2%, 96% have healthy children) but this is doubled, not a 2% increase

Risk for the community is an extra 2% incidence (i.e. with 2,000 consanguineous births each year, an extra 40 children with autosomal recessive conditions)

Every Baby Matters Initiative in Bradford Bradford district Infant Mortality report: Review of data on births and

deaths between 1995-03 and found that babies in Bradford:- 1.7 times more likely to die in their first year than babies born in

England and Wales as a whole. ( 2001-3 figures) more likely to die from congenital anomalies, infections and other

specific conditions born to Pakistani-origin mothers were twice as likely to die in their

first year of life compared to caucasian mothers as a whole – this increased burden of infant mortality is seen across England and Wales as well as in Bradford.

64 infant deaths across the District a year between 1996 and 2003 When compared with England as a whole, predicted total number

of deaths 41 Approximate excess of 23 deaths a year in Bradford.

Aim of Every Baby Matters Initiative in Bradford 10 Recommendations (Genetics no. 7) 58 % of Bradford’s births (approximately 5,000 a year)

are from the two most deprived quintiles and our challenge is to decrease the numbers of babies that die within these births by 10%.

‘To make sure that all parents with one child with an inherited disorder will understand the risk of a future baby carrying a similar disorder, and be in a position to make an informed choice about having another baby.’

Info in Leaflet : Be genetics aware!

Families from all communities can be affected by genetic disorders We know more about genes today than we used to, so it's right that we have access to

information and services so we can make informed choices There are many health problems associated with genes but, in infant health, there is a

particular concern with problems caused by recessive genes Common examples of these types of conditions include cystic fibrosis, sickle cell disease,

thalassaemia and some neurological and metabolic diseases For conditions caused by recessive genes, the risk is higher in families with a marriage to

a close relative, e.g. a cousin, as it is more likely they both carry the same gene It's important to note that most children born to cousins are healthy and unaffected, but

babies born to parents who have the same recessive gene are at a higher risk of being born with an inherited health problem and some rare recessive conditions can prove fatal

Talk to your GP if you think that a child in your own or your wider family may have been affected by an inherited disorder.

Your GP can help you to assess the risks and if necessary book you an appointment with a genetic counsellor

A genetic counsellor will be able to give a more rounded picture about your risk of genetic problems and what your choices are around this

Counselling in primary care

Explore what they know and want to know ‘Screen’ family history Any history of known recessive disorder? Remember to ask about family history of:

1. Miscarriages and still births 2. Birth defects (such as cleft lip, heart defects, spina bifida,

limb abnormalities) 3. Blindness/vision loss/deafness/hearing loss at a young

age4. Developmental delay/ learning disorders5. Regular attendance at CDC / OPD or visits from outreach

team e.g. Metablic

•

Counselling in Primary Care

If no significant family history:Can counsel re general riskOffer screening according to ethnicity No other specific testing possible

If possible / significant family history:Are they pregnant? If pregnant and would affect

decisions then refer urgently i.e. phoneWhat do they want to know?Can offer routine referral otherwise.

Resources for patients

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

genetic disorder

[email protected]

Genetics in Primary Care Dr. Jude Hayward GPwSI in Genetics, YRGS Dr. Brooke & Ptrs, Bradford.

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Transcript of Genetics in Primary Care Dr. Jude Hayward GPwSI in Genetics, YRGS Dr. Brooke & Ptrs, Bradford.