Download Clinical genetics in primary care practice

Clinical genetics in
primary care practice
Dr Emma Wakeling
Consultant in Clinical Genetics
North West Thames Regional Genetics
Service
Clinical genetics in primary
care practice: Aims
• Understand core genetic concepts
• Be able to take a family history and draw a
pedigree
• Understand the genetic referral process
• Be able to carry out a basic cancer risk
assessment using guidelines
• Understand some of the ethical issues
arising in genetics
• Be aware of other information resources
Genetics in primary care
• 1 in 10 patients seen in primary care has a
disorder with a genetic component.
• Many common disorders (eg: coronary
heart disease, diabetes, cancer,
Alzheimers) have a genetic component.
• Patients seeking advice regarding genetic
disease commonly present to their GP.
Genetics in primary care
Identifying
patients
Communicating
genetic
information
Clinical
management
Genetics in primary care:
patient care pathway
General practice
Identifying patients
and families with, or
at risk of, genetic
conditions
Indications for
referral to specialist
Hospital
General practice
Making diagnosis
Treating/managing
Condition
Ordering and
understanding
genetic test results
Recommending
treatments
Implications for
patient with
condition and for
other family
members
Referral to the genetic clinic
North West Thames Regional
Genetics Service
• Integrated Clinical
Genetics service: including
cytogenetic & molecular
labs
• Based at North West
London Hospitals NHS
Trust
• Covers North West
London, Hertfordshire &
Bedfordshire
• Consultants, SpRs, GCs
Role of clinical geneticist
Give information
• What is the condition?
• Explain inheritance
• Discuss chance of happening again
• Talk about treatment and prognosis
Role of clinical geneticist
Talk about choices
• Whether to have genetic tests
• Whether to have more children
• Whether to have tests during pregnancy
Role of clinical geneticist
Offer support to all the family
Common reasons for referral
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Family history of a genetic disorder
Family history of cancer
Consanguinity counselling
Abnormal genetic test result
Diagnosis in individuals with unexplained
learning difficulties and/or malformations
and/or dysmorphic features
• Fetal abnormality
Common reasons for referral
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Family history of a genetic disorder
Family history of cancer
Consanguinity counselling
Abnormal genetic test result
Diagnosis in individuals with unexplained
learning difficulties and/or malformations
and/or dysmorphic features
• Fetal abnormality
If you need advice
• Phone us – 0208 869 2795
– A Consultant is always on call 9-5 Mon-Fri
• We are friendly and happy to give advice
• Fax us – 0208 869 3106
– All urgent referrals
• Pregnancies
Taking a family history
Family history
Diagnosis
Mode of
inheritance
RISK
Test results,
age, etc
Family history
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How many generations affected?
Which genders affected?
What proportion affected?
Male to male transmission?
Pedigree symbols
male
female
sex unknown
. .
affected
carriers
couple
consanguineous couple
identical twins
deceased
miscarriage
Tips for taking a family history
• Information on 3 generations
• Ask about consanguinity
• Remember to include stillbirths and
miscarriages
• Get as much information as possible
about affected relatives or potential
carriers
Chromosomal anomaly
Single Gene Defect
Chromosome translocations
• 1 in 500 individuals have a
balanced chromosome
translocation
• Usually healthy
• But at risk of:
• infertility
• miscarriage
• live born child with
learning difficulties and
other problems
Translocations:
pregnancy outcomes
del (blue)
dup (purple)
Normal
Balanced
translocation
carrier
del (purple)
dup (blue)
Mendelian inheritance
• Everyone has 2 copies of each
gene (alleles)
• Parents pass on one copy of
each gene to their children
Mendelian inheritance
• Modes of inheritance:
• Autosomal dominant
• Autosomal recessive
• X-linked
Single gene disorders
•Dominant disorders more likely to be
structural and variable in degree
•Recessive disorders often biochemical
and tend to breed true
•X-linked disorders sometimes detectable
in female carriers
Autosomal dominant inheritance
Autosomal dominant inheritance
• Affected individuals in each
generation
• M or F affected, with equal
severity
• 50% siblings affected
• 50% offspring affected
• Male to male transmission
Eg:
AD Polycystic kidney disease
Huntington’s disease
Familial breast cancer (BRCA1/2)
Marfan syndrome
Variable penetrance
Penetrance: the proportion of individuals
with a particular genotype who show an
abnormal phenotype.
Eg: BRCA1 mutation in women gives 80-90%
lifetime risk of breast cancer & 40-50%
lifetime risk of ovarian cancer.
Penetrance may appear to be reduced due to
late onset of the disorder- eg: Huntington’s
disease.
Neurofibromatosis type 1
Autosomal recessive inheritance
Autosomal recessive inheritance
• Usually only one
generation affected
• M or F affected, with equal
severity
• 25% recurrence risk for
siblings
• Unaffected siblings have a
2/3 chance of being
carriers
E.g: Cystic fibrosis
Sickle cell disease
Haemochromatosis
Autosomal recessive inheritance:
calculating carrier risks
1/2
1/2 1/4
1
1
1/2
2
2/3
1
1/2
Autosomal recessive
inheritance is more common if
there is consanguinity
1st cousin parents have a 1/32 (~3%) chance of having
a child affected by an AR condition
Ethnicity and Genetics
• Particular races tend to consanguinity
– Irish Travellers 90%+
– Pakistani 60-70%
– Tamil 20-40%
– Somali
• Do not assume, but it’s good to ask.
Ethnicity and Genetics
• Sub Saharan Africa
– Sickle Cell
– G6PD Deficiency
• Mediterranean
– Beta Thalassaemia
• Indian Sub-Continent
– Beta Thalassaemia
• South East Asia
– Alpha and Beta Thalassaemia
Ashkenazim- carrier frequency
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Gaucher (1 in 11)
Tay Sachs (1 in 25)
Cystic Fibrosis (1 in 25)
Canavan (1 in 40)
3 mutations BRCA 1 and 2 (1 in 40)…..
X linked inheritance
X-linked recessive inheritance
X-linked recessive inheritance
• Only males affected
• Female carriers (usually)
unaffected
• Carrier females have a 50%
risk of having an affected
son and 50% risk of having
a carrier daughter
• All daughters of an affected
male are obligate carriers
• No male to male
transmission
E.g: Haemophilia
Duchenne Muscular Dystrophy
• What is the inheritance pattern?
• What is the chance of this individual being
affected if they are
- male?
- female?
• What is the inheritance pattern?
• What additional information might be useful?
Mitochondrial inheritance
• NOT Mendelian
• Ova contain mitochondria,
sperm do not
• Maternally inherited but can
affect both males and
females
• Mitochondrial rich tissues
frequently affected
• Severity very variable and
unpredictable
Common diseases
• Genetic component to many common diseases
including:
• Coronary heart disease
• Diabetes
• Cancer
• Some families may have underlying single gene
disorder. Eg:
• Familial hypercholestrolaemia
• Breast cancer (BRCA1/2)
• Colon cancer (Lynch syndrome, FAP)
• Need to identify those in whom genetic testing
may help modify management
• Eg: Rx, screening, prophylactic surgery
Familial cancer
Familial Breast Cancer
Around 5% cases of breast cancer have a strong
familial predisposition.
75
45
Harold
87
June
85
Patrick
Isabel
Breast Cancer
58
Michael
48
Doris
65
Dennis
64
Marjorie
68
Jennifer
70
Hannah
Prostate Cancer Ovarian Cancer
35
Marie
Breast Cancer
38
Edward
40
Jane
43
Susan
Breast Cancer
86% chance
BRCA1 /BRCA2 mutation
A family history of breast cancer
Familial bowel cancer
• Around 15-30% of cases have a familial
predisposition
• Only around 5% of cases due to single gene
disorder eg: Lynch syndrome (HNPCC), familial
adenomatous polyposis
• Lynch syndrome associated with
– Young onset bowel cancer
– Other cancers, eg: endometrial, ovarian, renal, etc
– Multiple affected individuals in several generations
Referrals for familial cancer
http://www.nwlh.nhs.uk/nwthamesgenetics/CancerReferral.html
• Any individual with a family history of a
known mutation
– Unless an intervening relative has tested
negative
• Affected relatives MUST be blood relations
of each other, but can be through the
maternal OR the paternal side.
Breast Cancer Families
• Single case <40 years
• Two cases of breast cancer diagnosed under
the age of 60
• Three or more cases of breast cancer
• Breast cancer and ovarian cancer. This includes
any case where a patient gets both cancers
• Any male breast cancer cases with a relative
affected with breast cancer (male or female)
• Ashkenazi Jewish with any family history of
breast or ovarian cancer
Ovarian Cancer Families
• Any family with two or more cases of
ovarian cancer
• Any family with ovarian cancer and
colorectal cancer, endometrial cancer or
breast cancer under the age of 50
Bowel Cancer Families
• Families with colorectal cancer and either
endometrial cancer and/or ovarian cancer
and/or breast cancer
• Two cases of colorectal cancer
• Single case of colorectal cancer aged <45
years
Other Cancer Families
• Any other families with an unusual pattern
of cancer in the family (eg: multiple
individuals with melanoma)
• Rare syndromes
– MEN, Von Hippel Lindau, Li Fraumeni
• Unusually young age at diagnosis for the
particular cancer
Genetic testing
Genetic Testing
• Confirmation of diagnosis
• Carrier testing
• Presymptomatic testing
NWTRGS laboratories
• Cytogenetic laboratory
– Chromosome analysis (karyotype, microarray)
– Handle samples for prenatal testing (CVS,
amniocentesis)
– Diagnosis and monitoring in haematological
samples (eg: AML)
NWTRGS laboratories
• Molecular genetic laboratory
– DNA storage
– Testing eg: Cystic Fibrosis, Fragile X syndrome
– CF screening programme
– Export of samples to other UKGTN laboratories
UK Genetic Testing Network
Genetic testing
• Testing usually only done on an affected
individual as first line
• A single diagnosis may be caused by multiple
genes
• A negative result may not always exclude the
diagnosis
• Not always clear whether a gene change is
causative
• May take several months or sometimes years
if done on a research basis
DDD study
Aims to advance
clinical genetic
practice for children
with developmental
disorders using the
latest microarray and
sequencing methods
while addressing the
new ethical
challenges raised
Antenatal screening
Newborn screening
Blood spot screening
Down syndrome
• Nuchal translucency
• PKU
• Congenital hypothyroidism
• Sickle cell disease
• Blood test
• Cystic fibrosis
Sickle cell and thalassaemia
• MCADD
Fetal anomaly scan
Hearing
Physical examination
Genetics in primary care:
patient care pathway
General practice
Identifying patients
and families with, or
at risk of, genetic
conditions
Indications for
referral to specialist
Hospital
General practice
Making diagnosis
Treating/managing
Condition
Ordering and
understanding
genetic test results
Recommending
treatments
Implications for
patient with
condition and for
other family
members
Management of
genetic conditions
in primary care
Management of genetic
conditions in primary care
• Reassurance
• Managing uncertainty
• Reproductive options
• Prenatal diagnosis, pre-implantation genetic diagnosis,
ovum/sperm donation, adoption
• Coordination of patient-centred care
• Support services, appropriate referral to specialist care
• Prevention
• Screening, surveillance
• Treatment
Support for patients
Support for patients
Support for patients
Ethical issues in
genetic medicine
Ethical issues in genetic medicine
• Emphasis on prevention/ early detection of
disease within primary care
• Family centred care
• Increasing patient focus on autonomy and
confidentiality
• Need to balance conflicting duties to
individual patients who are members of
same family
Case history 1
Patient autonomy and the
right to confidentiality
Consent and confidentiality
• Usually ask individuals to share information
with relatives
• Offer support mechanisms
• But..
• Non-disclosure
• Relatives may not want to pursue testing
Consent and confidentiality
• Professional guidelines (GMC) & UK law:
preventable harm to others places a limitation on
duty of confidentiality
• Prevention of serious harm relates to:
• Treatment/ screening
• Child bearing choices
• Prenatal diagnosis
• Many cases resolved by working with the patient
to highlight the importance of disclosure, while
offering support
Communication of
genetic information
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Understandable
Non-directive
Confidential
Sensitive to cultural
and religious views
Case history 2
Finding unexpected
information
Non-paternity
• Information has direct implications for both
parents
• Problems with non-disclosure
• Couple unable to make autonomous choices
• May make misinformed choices- eg: decide to go ahead with
prenatal testing
• Paternalism vs non-malevolence
• Ideally discuss possibility of finding non-paternity
prior to testing
• Exclude rare genetic mechanisms presenting
like non-paternity/ sample mix up
• Approach sensitively!
Case history 3
Genetic testing in children
and indirect testing
Genetic testing in children
• Is the test in the child’s best interests?
• Could the test do more harm than good?
• Is it possible to wait until the child is old
enough to decide for himself whether or
not to have the test?
Genetic testing in children
• Beneficial if:
• Confirming a suspected diagnosis
• Removing the need for invasive testing (eg:
FAP)
• Problematic if:
• Carrier testing in a healthy child
• Predictive testing for an adult onset condition
Reasons for deferring a test for HD in Ben
at present:
– Adult onset condition
– No interventions to alter the course of the
disease
– Testing before Ben can consent denies him a
choice as an adult
– If Ben tests positive he reveals his father’s
genetic test result
Case history 4
Prenatal genetic diagnosis
• UK law recognises a woman’s right to chose to
test her baby in pregnancy and whether to
terminate a pregnancy
• Explore reluctance to disclose information
• Discuss alternatives to termination of pregnancy,
eg: pre-implantation genetic diagnosis (PGD)
Genetic information and
discrimination
• Reluctance to take DNA tests because of
fears of stigmatisation by eg: employers,
insurance companies
• UK insurance industry self-imposed
moratorium until 2017- cannot ask for
genetic test results*
• Family history of disease can be used to
load/ refuse premiums. Not asked for by
all companies
* Except HD- Life insurance policies >£500,000, other policies > £300,000
www.nwlh.nhs.uk/nwthamesgenetics/
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Contact details
Clinic locations
Patient information
Cancer referral guidelines
– Family history questionnaire
• Laboratory information
– Sample referral forms
Useful references
• www.nwlh.nhs.uk/nwthamesgenetics/
• www.geneticseducation.nhs.uk/
• Oxford Handbook of Genetics
Guy Bradley-Smith, Sally Hope, Helen V. Firth, and Jane A. Hurst