Genetics for GPR’s

Thank you for inviting me…

Susan FairgrievePrincipal Genetic Counsellor

1.Highlight the relevance of genetics to your practice

2.Review skills in taking and interpreting family histories (discussing cases)

3.Making a referral

Aims

Recognition from RCGP

Clinical management

Communicating genetic information

Identifying patients

What do you encounter?

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 ?

On average - how many consultations relating to family cancer do GPs have every year?

1 in 20 before the age of 25, 60% in later life have conditions with a genetic component

Common / Important ConditionsChromosomal disordersSyndromes: Down’s, Edward’s, Patau’s, Turner’s, Klinefelter’s. Chromosomal Translocations

Autosomal dominant disordersFamilial HypercholesterolemiaHuntington’s DiseaseMarfan’s SyndromeNeurofibromatosis

Familial CancerBowel/Uterine/Ovarian ?HNPCCBreast/Ovarian/Prostate ?BRCA1/2

Autosomal recessive disordersCystic FibrosisHaemoglobinopathiesHaemochromatosis

X-Linked disordersDuchenne Muscular DystrophyHaemophilia AFragile X syndrome

Variable inheritance patternsDeafness

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

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

What does a genetics service offer?

• Genetic Testing

• Diagnosis

• Genetic counselling

• Patient information

• Speciality services and clinics

• Education and training

• Telephone advice

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

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

What happened?

• Bloods for Chromosomes sent

• Male partner’s report states that the quality of the sample was such that they could not exclude any subtle translocation

• Female partner normal karyotype

Reciprocal Translocation

Normal Carrier Unbalanced Unbalanced

7 7 10 10 107 der7 der10

7 7 10 10 107 der7 der10 7 der7 10 10 7 107 der10

Genetic Testing

• Diagnostic

• Carrier

• Prenatal

• Pre-implantation Genetic Diagnosis

• Predictive

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

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

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

Chorionic Villus Sample

Amniocentesis

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

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

Case study:

Is my baby at risk of cystic fibrosis?

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

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

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

Family History

• Jane (28) is 6 weeks pregnant

• Jane’s husband is Christopher (29)

• This is their first baby

Jane28

Christopher Hobson29

P

6 weeks

Family History

• Christopher is an only child.• • His father is William (60)

• His mother is Margaret (59)

• They are both alive and well

Jane28

Christopher Hobson29

William Hobson60

Margaret59

P

6 weeks

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

George WhiteheadDied age 66

Joan64

John Whitehead34

Jane28

Christopher Hobson29

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

George WhiteheadDied age 66

Joan64

John Whitehead34

Jane28

Christopher Hobson29

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

George WhiteheadDied age 66

Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic Fibrosis

9 weeks

Christopher Hobson29

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

Christopher Hobson29

William Hobson60 59

P

6 weeks

Alice33

David10

Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk

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

Christopher Hobson29

William Hobson60

Margaret59

P

6 weeks

Alice 33

David10

Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk

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

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

alteration for CF

1

100

1

25

XX

X X =

=

George WhiteheadDied age 66

Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic fibrosis

9 weeks

Christopher Hobson29

William Hobson60

Margaret59

P

6 weeks

Alice33

David10

When should specialist genetic advice be sought?

George WhiteheadDied age 66

Joan64

John Whitehead34

Jane28

Christine 29

Richard4

Cystic fibrosis

9 weeks

Christopher Hobson29

William Hobson60

Margaret59

P

6 weeks

Alice33

David10

Which other family members should be offered carrier status testing?

Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk

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

Alpha1 Antitrypsin Deficiency

• MSZ Phenotype

• SZ and ZZ – Advise re: smoking and alcohol– Check baseline lung function