genetics: what do you need to know in practice? anita bruce and kate simon genetic counsellors north...
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Genetics:What do you need to know in
practice?
Anita Bruce and Kate Simon
Genetic Counsellors
North East Thames Regional Genetics Service
Summary
• Genetics Services• Genetics and Disease• Inheritance and common genetic
conditions• Genetics and Cancer• Family History• Some more complex issues
Why should I be concerned about genetics?
• RCGP Curriculum Statement 6– Genetics in Primary Care
• A significant minority of any practice population will include patients who have (or are at risk of) a genetic condition.
• Genetic diseases and congenital malformations account for:– 2-5% of live births– 30% paediatric admissions
• Chronic disease with a significant genetic component:– 10% of adult population
Structure of Genetics services
Clinical Genetics• Consultants• Genetic Counsellors• SpR’s
Cytogenetics• chromosomes• scientists
Molecular Genetics• DNA• scientists
GPs• Identify• Tx individual• Manage family
Genetic Clinics in NE ThamesCancer Genetics Clinics General Genetics Clinics
Why are people referred?• Child:
– Birth anomalies– Dysmorphic features– Learning difficulties.
• Adult:– Diagnosis– Predictive testing– Carrier testing– Family history (including cancer)– Fetal loss or recurrent miscarriages.
• Pregnancy:– Known genetic disorder– Abnormality detected on screening.
What is genetic counselling?
• Not counselling in traditional sense• Specific information to convey • Difficult concepts to explain • Many factors affect effectiveness of
session including family relationships / dynamics
• Genetic disease may evoke complex emotions in an individual
Making a genetic diagnosis
• Family tree– to detect a pattern of inheritance
• Physical examination– to give precise diagnosis
• Genetic tests– Chromosomes (karyotype)– Genes (DNA testing)
Talk about choices
• Non-directive and non-judgemental
• Confidentiality
• Family Service
• Multifactorial“Environmental” influences act on a genetic predispositionOne organ system affected
• Single geneDominant / recessive pedigree patternsStructural proteins, enzymes, receptors, transcription
factors
• ChromosomalMultiple organ systems affectedInherited or de novo
• EnvironmentalDrugs, infections
GENETIC ENVIRONMENTAL
Duchenne muscular dystrophy
HaemophiliaOsteogenesis imperfecta
Club footPyloric stenosisDislocation of hip
Peptic ulcerDiabetes
Tuberculosis
PhenylketonuriaGalactosaemia
Spina bifidaIschaemic heart diseaseAnkylosing spondylitis
Scurvy
The contributions of genetic and environmental factors to human diseases
RareGenetics simple
UnifactorialHigh recurrence rate
CommonGenetics complexMultifactorialLow recurrence rate
Genetic disorders: reproductive choices
– no (more) children – accept risk– prenatal diagnosis– adoption– gamete donation– preimplantation genetic diagnosis
Prenatal diagnosis for genetic disorders
• A genetic diagnosis does not always mean a prenatal test is possible
• What is the accuracy of the test?• Do the parents understand what will be
tested for, the risks and limitations of the test?
Prenatal diagnosis: psychosocial impact
• Parents often feel conflict and guilt about their affected child
• Issues around termination of pregnancy• May have experienced several pregnancy
losses • Remember “chance has no memory”
Prenatal testing: other considerations
• Unexpected results: testing for one condition but may detect a different one
• Revealing unexpected / unwanted information
Autosomal Dominant Inheritance
• Each child has a 50% chance of inheriting the mutation
• Men and women equally affected
• Equally transmitted by men and women
• Multiple generations
AffectedAffected
Normal Normal
Huntington’s Disease
• Movement / Cognitive / Psychiatric Disorder• Mean age of onset 35 - 55 years• Incidence of 1 in 10,000• Diagnostic and presymptomatic testing available
Case study Diagnostic testing for Huntington’s disease
Diagnosis has implications for children as now at 50% risk
Need to consider wider family
Autosomal recessive inheritance
• Males and females equally affected• Individual must inherit two mutations (one from each
parent) to have condition• Carriers are unaffected• Each child of 2 carrier parents has a 25% chance of
being affected
Noncarrier individualNoncarrier individual
Non-affected carrierNon-affected carrier
Affected individualAffected individual
Cystic Fibrosis • Clinical Features
– Pulmonary and digestive manifestations– Infertility in 98% affected men
• Incidence of 1 in 2500 (carrier frequency 1 in 25 in N. European population)
• Genetic Testing – Common mutation panel picks up 90% mutations in individuals from N
European origin
Case Study
First child affected with cystic fibrosis.
Child is a compound heterozygote for delta F508 / W1282X
11/40 weeks pregnant, requesting PND
Case Study
Parental genotyping:
Mother: N / W1282X
Father: N / N
Case study
• Non-paternity• Who would you give the result to?• What are the arguments in favour for and
against disclosure?• What would you do?
Lessons
• Technical problems are relatively rare• Parents often feel conflict and guilt about
their affected child• Fetal loss is always traumatic• There is no secure way to guarantee a
good outcome• The difficulties within families may not be
avoidable
Connexin 26 Deafness
• One of the most frequent causes of bilateral sensorineural hearing loss
• Carrier frequency of 1/30 to 1/70
• Variable
X-linked inheritance
• Altered gene is on the X chromosome• Only males affected (usually)• Affected males linked through unaffected females
Carrier femaleCarrier female
Affected maleAffected male
Normal maleNormal male
Duchenne Muscular Dystrophy
• Progressive muscle weakness
• Mainly in a wheelchair by early teens
• Respiratory muscles eventually involved
• Death usually in late teens, early twenties
Case Study – JoDuchenne muscular dystrophy
16 weeks
Issues
• Family history was well documented• How was she missed?• We cannot depend upon family
communication• Consequences include:
– loss of reproductive choice – risk of having an affected child – health considerations as risk of cardiomyopathy
in carriers
Fragile X Syndrome
• Mild-severe learning difficulties
• Characteristic facies; macro-orchidism
• Incidence 1 in 5000 males– CAN affect females
(but milder LD)
Chromosome Anomalies• ~1% live births affected (5% stillborn; 50% spontaneous
abortions)
• Numerical– Trisomies (eg. Down, Edward syndromes)– Sex chromosome aneuploidies (eg. Turner, Klinefelter syndromes)
• Structural– Translocations (balanced or unbalanced)– Inversions– Deletions/Insertions
Presymptomatic testing
• Relatively new development• Individual has no signs of disease• Has FH of disease• Wants to know if will develop it• Mainly done for Huntington’s disease and
some familial cancer/cardiac syndromes
Presymptomatic testing for HD
• First offered in 1987; accurate mutation analysis since 1993
• Can tell if someone has inherited the faulty gene or not
• Does not accurately indicate age of onset/severity
Presymptomatic testing for HD - potential problems after test
• Depression• Difficulty in adjusting to result• Regret• Family breakdown• Suicide
Presymptomatic testing for HD - ethical issues
• Is it ethical to tell someone they are going to develop a disease when we have no preventative treatment?
• Can we refuse to test?• Age limit for testing
Genetic testing in childhood: ethical considerations
• Child’s autonomy: the right of the child to decide
• Confidentiality of genetic information• Discrimination
Genetic testing in children: 3 key questions
• 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 so that they can decide for themselves whether to have the genetic test?
Genetic testing in children: diagnostic
• May avoid other investigations and aid management
Genetic testing in children: carrier
• Unlikely to alter management• Generally recommended to postpone until
age when they can understand implications
Case Study: carrier testing
First child has AR genetic condition. Want prenatal test for future pregnancies.
Healthy siblings tested as part of the work up for a prenatal test
Case Study: carrier testing
Father telephones department and asks for carrier results of sons.
Mother calls next day and asks for him not to be told as concerned how it will affect his interaction with their sons.
Carrier Non-carrier
Genetic testing in children: presymptomatic
• Should only be done if useful medical intervention to prevent or modify course of disease would be offered during childhood
• Postpone testing until child able to understand or screening begins
• Not appropriate for HD• Offered for a some inherited cancer
syndromes & cardiac disorders
Genetic testing
• Provides information• May alter management• May allow reproductive choice• May be a burden• Should be used with caution
Introduction to Cancer Genetics
Do Genes Affect Cancer Risk?
How Many Cancers are Genetic?
Sporadic (~85%)
Familial (~10%)
Hereditary (~5%)
Genetic Cancers• Breast and ovarian• Colon cancers• Cowden syndrome• Gastric cancer• Gorlin Syndrome• Li-Fraumeni• Multiple endocrine neoplasia (MEN)• Neurofribomatosis• Peutz-Jeghers syndrome• Pheochromocytoma• Retinoblastoma• von Hippel-Lindau disease• Wilm’s tumour
What are the cancer risks for the general population?
• 1 in 3 people will develop cancer at some point in their lives
– Prostate: 17% – Female Breast: 12-13% – Lung: 6-8%– Colorectal cancer: 6%– Melanoma: 1-2%– Ovarian: 1.5%– Stomach / Pancreas: 1%– Male breast: 0.1%
SEER Figures. NCI 2001-2003
Sporadic Cancer
• Majority of cancer cases (~85%)
• Usually not inherited
• Age of diagnosis typically later in life
Familial Cancer• 2 or more affected 1st
or 2nd degree relatives
• Later onset common• Risk 2-3 times general
population
Causes of Clustering? Environmental? Chance? Hereditary
Hereditary Cancer Multiple generations
are affected on one side of the family
Several affected family members
Earlier than average age of onset
Individuals with more than one primary tumour site
A particular pattern of cancers noted
5-10% of Cancer Cases
Most Cancer Susceptibility Genes Are Dominant With Incomplete Penetrance
• Penetrance can be incomplete• May appear to “skip” generations• Individuals inherit cancer susceptibility
genes, NOT CANCER.
Normal
Carrier, affected Ca
Sporadic Ca
Susceptible Carrier
Hereditary Breast and Ovarian Cancer
Sporadic
AJHG 1998;62:676-89JCO 2002;20:1480-1490
BRCA1BRCA2
5-10%
Hereditary
Most cases caused by a BRCA1 or BRCA2 mutation
Other genes
What do BRCA1 and BRCA2 do?
BRCA1/BRCA2 proteins are involved in the repair of DNA damage
Belong to a class of genes known as tumour suppressor (TS) genes
TS genes regulate the cycle of cell division by keeping cells from growing and dividing too rapidly or growing in an uncontrolled way
BRCA1-Associated Cancers:Lifetime Risk
Possible increased risk of other cancers (eg, prostate in men)
Breast cancer 60%-80% (often early age at onset)
Second primary breast cancer 64%
Ovarian cancer 20%-40%
BRCA2-Associated Cancers: Lifetime Risk
Increased risk of prostate (?10-20%) and pancreatic cancers (?3%)
breast cancer (50%-80%)(50%-80%)
ovarian cancer (10-30%)(10-30%)
male breast cancer (7%)(7%)
contralateral breast (50%)(50%)
Options for BRCA1/2 Carriers
• Cancer Screening – Additional breast screening by mammography / MRI
– Ovarian screening through UKFOCSS research trial
• Prophylactic bilateral mastectomy– ~90% reduction in breast CA risk
• Prophylactic bilateral salpingo-oophorectomy – ~up to 96-98% reduction in ovarian CA risk
– ~50% reduction in breast CA risk (age dependant)
• ? Chemoprevention in the future
• ? Tailoring of treatment for carriers in the future
Genetic testing• For families fulfilling the criteria we can offer a blood test
looking for mutations in BRCA1 and BRCA2
Usually start by testing an affected patient!
• Does not rule out hereditary cancer• Different testing methods available:
– Ashkenazi Jewish mutations– Research studies
Risk categories
Following assessment of family history, patients can be placed into different risk categories
This will determine whether or not they will have an appointment and whether testing be offered
In order to be offered genetic testing, there must usually be a 20% + chance of finding a BRCA mutation
It also helps determine screening recommendations Population risk - standard population breast screening from 50 Moderate / High risk – additional breast screening from ~ 40 +/-
UKFOCSS
When to refer • 2 first or second degree relatives with breast
cancer < 50 yrs• 3 first or second degree relatives with breast
cancer < 60 yrs• 4 relatives with breast cancer at any age• 1 ovarian cancer at any age + 1 breast cancer < 50
yrs• 1 ovarian cancer + 2 breast cancer both < 60 yrs• 2 ovarian cancer any age• Patients who are thought to be of Ashkenazi
Jewish heritage with at least one first degree relative with breast cancer <50 years or ovarian cancer any age
• NB bilateral breast primaries equivalent to 2 relatives
Case 1: Ruth
Ruth, a 35 year old Ashkenazi Jewish woman, comes because she is anxious about her family history of cancer. You inquire about family health history and find out the following information:
– Paternal family history is as follows:• Paternal grandmother diagnosed with
ovarian cancer at age 63• Paternal aunt diagnosed with breast
cancer age 42
Ruth has no other risk factors or pertinent family history
Case 1: Pedigree
Key
-Ov Ca
-Br CA
Dx 6382 yrs
Ruth35
Russian Jewish
Polish Jewish
41 38
60 58Dx 42
64yrs
Case 1: Assessment
• Patient is in “Moderate risk” category• However ethnicity is important as she is of
Ashkenazi Jewish descent
• Refer to genetics clinic• Moderate risk screening for breast cancer
arranged• Genetic testing for 3 common ‘Jewish
Mutations’
Case 2: Ann
• Ann has come along because her sister has ovarian cancer, sadly the cancer has spread. Her family history is a follows:
• Sister diagnosed with ovarian CA at 53 yrs• Mother diagnosed with ovarian CA at 61 yrs and
has sadly died• Maternal aunt diagnosed with breast cancer at 48
yrs
Ann has no other risk factors for breast cancer. She feels that with her family history, cancer is inevitable
Case 2: Pedigree
2
49OvCa Dx 53
OvCa Dx 61
Died 64
2
3
30s39
BrCa Dx 48
6573
Case 2: Assessment
• Patient is in “High” risk category• Refer to genetics clinic promptly
• High risk screening breast and ovarian cancer
• Genetic testing offered
Case 3
• Which side of the family are you worried about?
• What surveillance does she need?
Both
Breast and ovarian screening
She actually had two BRCA mutations!
Case 4: Alison
Alison is a 40 year old Caucasian (non-Jewish) patient who asks you for information about the “breast cancer gene test”. She states she wants this test.
You ask about her family history:
– Mother with breast cancer - age 58
– Maternal aunt with breast cancer – age 65
– Paternal grandmother with breast cancer – age 79
Alison has no other risk factors for breast cancer
She feels that with her family history, breast cancer is inevitable
Case 4: Pedigree
Dx 5865 yr
Dx 6571 yr
Dx 79d.81
Key:
-Breast CA
Alison40 yr
15 yr
Case 4: Assessment
• Patient is in “Moderate” risk category• Refer to breast clinic for breast cancer
screening from 40-50 years then NBSP • Counselling issues:
– Unlikely to be due to a BRCA1 or BRCA2 mutation
– Screening and preventive strategies – Psychosocial – perceived risk, fears – Support resources
Colorectal Cancer
Sporadic (~60%)
Familial (~30%)
HNPCC (3-5%)FAP (~1%)
MAP (~1%)
Rare Syndromes
(~4%)
HNPCC or Lynch syndrome
• 2-3% of all colorectal cancer cases
• Autosomal dominant; high penetrance
• Typical age of CA onset is 40-50 yrs
• Multiple affected generations
• 60-70% right-sided/proximal CRC tumors
• Polyps may be present, multiple primaries common. Can overlap with AFAP
HNPCC
• Lifetime cancer risks: – Colorectal 80%
– Endometrial 20-60%
– Gastric 13-19%
– Ovarian 9-12%
– Biliary tract 2%
– Urinary tract 4%
– Small bowel 1-4%
– Brain/CNS 1-3%
HNPCC
Caused by mutations or deletions in mismatch repair (MMR) genes
MSH2, MLH1, MSH6, PMS2
90% of detectable mutations in MSH2 and MLH1
7-10% of detectable mutations in MSH6
MMR genes are like spell checkers in our DNA
Options for individuals with HNPCC
• 1-2 yearly colonoscopy
• Ovarian and endometrial screening (not proven to be effective)
• ? renal/upper GI screening effective (if have history of gastric/renal cancers)
• Surgery– Prophylactic bowel surgery not often chosen– Total abdominal hysterectomy and salpingo-
oophorectomy for females
Familial adenomatous polyposis (FAP)• 1 in 10,000 incidence
• 100’s to 1000’s of colonic adenomas by teens
• 7% risk of CRC by 21 yrs; 93% by 50 yrs
• 20-25% no history in parents• Extra-colonic features• Screening
– 1 – 2 yearly flexible sigmoidoscopy from age 10 – 12
– Upper GI endoscopy 1 –3 yearly from age 25
MAP syndrome/MYH gene
• MYH associated Polyposis (MAP) syndrome
– Autosomal recessive; mutations in the MYH gene
– Median number of polyps = 55
– Mean age of polyp diagnosis = 30-50 years
– Polyps mainly small, mildly dysplastic tubular adenomas. Some tubulovillous, hyperplastic, serrated adenomas, microadenomas
• 30% of individuals with 15-100 polyps have homozygous mutations in the MYH gene
• Genetic testing should be offered if >10-15 polyps (and APC gene testing negative)
When to refer• Patient or 1 first degree relative affected with
– Colorectal cancer <50yrs
– 2 or more colorectal primary cancers any age
– Colorectal cancer and a related cancer* any age.
• 2 first degree relatives affected with colorectal cancer or related cancer* at any age
• 3 relatives affected with colorectal cancer or related cancer* at any age, one of which must be a first degree relative.
• History of Polyposis (e.g. Familial adenomatous Polyposis)
– *related cancers- endometrial, ovarian, small bowel, ureter, renal pelvis and stomach
Genetics and Uncertainty
• Genetic testing for increased susceptibility to cancer is still in its infancy
• It does not guarantee who will and who will not develop cancer
• It allows us to identify individuals who may be at higher risk of developing certain types of cancer
What Can You Do?
• Recognise patterns of cancers in families– Young onset– Lots of one or two particular types of cancer– Jewish?
• If not sure ask– Don’t be afraid to contact genetics for advice
• Take a blood sample for DNA banking
DNA Banking• DNA banking provides families with the chance to
pursue genetic testing at a later point in time
– where there is currently no genetic test available. DNA banking will allow the family to take advantage of future advances in genetic testing technology
– A family member diagnosed with cancer who is terminally ill and there is no time for traditional a genetic assessment and/or testing. The family can then focus their attention on their loved one and defer the process of genetic counselling and testing to a time when they are ready
Case 1• Helen has primary
ovarian cancer• Would this family
need seeing by genetics?
• What other cancer could she be at risk for?
YES
Colon and uterine cancers
Case 2
Key:
Endometrial CA
Colorectal CA
Adenomatous polyps
Dx 38
Dx 50
88 yr
63 yr
4 polyps50 yrs.
CRC Dx 48
61 yr
38 yr
10 yr 8 yr
35 yr
Lynch syndrome
Case 3: Ted
• Ted is 30 and wants a colonoscopy because his mother was just diagnosed with colon cancer after routine screening at age 54. Family history reveals:
– Paternal grandfather: died of CRC at age 79.
– No hx of endometrial, ovarian, small bowel or ureter/kidney cancer on either side of family.
– Two maternal aunts: cervical cancer at ages 30 & 34
– Maternal grandmother: breast cancer age 85
Reassure
Contact DetailsAnita BruceKate Simon
Genetic CounsellorsChurchfield 2Southend University HospitalPrittlewell ChaseWestcliff-on-SeaEssexSS0 0RY
email: [email protected] [email protected]
Tel: 01702 435 555 x6447Fax: 01702 385 832