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an overview of the service and GP
referral patterns
Dr Alan Fryer
September 2016
Diagnosis of genetic disorders
Genetic counselling
Advice re screening/surveillance
Not often involved in clinical management
Role in multi-system disorders?
Genetics and non-geneticists
• Diagnosis and genetic counselling is not
exclusive to clinical geneticists
• Many system specialists can and do cater for
the genetic aspects of their specialty disorders
– especially haematologists, lipidologists.
• Many specialists do not however feel that
they have the time or interest to do this – they
want to concentrate on ill people rather than
healthy relatives i.e. they are “treaters” rather
than “screeners”.
The local service
• Clinical – one service managed by LWH and
based at LWH
• Consultants and STRs in Clinical Genetics
• Genetic Counsellors – usually have a nursing
• Labs – unified Regional Genetics lab at LWH
(both cytogenetics and molecular genetics–
distinction between cytogenetics and
molecular genetics is now blurring).
–how do we do it?
• Largely an out-patient specialty but we do provide
in-patient consultations.
• Hub and spoke model – central base with outreach
• District clinics – Chester (adult and paeds); Crewe,
St Caths, Warrington, Ormskirk (paeds only).
• Specialty clinics – Neurogenetics (Walton Centre),
Cardiac Genetics (Liverpool Heart & Chest Hospital)
• Multi-disciplinary clinics
Referrals from Primary Care
(survey done in a month in 2008)
• Total referrals = 277 of which GP referrals = 63 (23%).
• Of the GP referrals only 12 were for symptomatic
• 28 were for a FH of cancer
• 2 others were for a FH of cancer and another disorder
GP referrals – symptomatic patients
• 1 a 50 yr old with hypercholesterolaemia asking about gene testing;
• 1 known case of MELAS re-referral about gene testing to assess level
of heteroplasmy;
• 1 with a child bit dysmorphic – could it be Downs?
• 1 had breast ca and had family history of breast cancer
• 1 with FH of paracentric inversion and has reduced fertility herself.
• 1 patient with Addisons, diabetes and FH diabetes -?any genetic link.
• 1 adult with learning difficulties and dysmorphic
• 1 boy aged 12 who has a limp and dad has Huntington’s Disease;
• 1 with ? Marfan diagnosed by cardiologist;
• 1 ? Marfan in patient
• 1 child referred – parents think he may have FRAX;
• 1 13yr old - ? Fetal alcohol
Referrals from primary care
• FH of Huntington’s disease 3
• FH Duchenne (teenage girls) 2
• FH Becker 1
• FH cystic fibrosis 3
• FH other issues :- 1 with FH of long QT and BRCA1 mutn; 1 with FH
of both PCKD and some form of muscular dystrophy; 1 – father died age 67
had HHT; 1 man and his 2 children FH of bowel cancer with FH of HMSN in
his mother and her family; 1 with FH of haemochromatosis; 1 with FH of
some form of muscular dystrophy; 1 FH Friedreichs ataxia; 1 FH long QT; 1
FH of fragile X; 1 FH of muscular dystrophy (dominant); 1 father who is a
beta-thal carrier; 1 from a health visitor with FH Ebstein anomaly; 1 FH of a
chromosome abnormality; 1 sister tested for autistic genes??
Referrals from primary care
• The “worried well”
• Reactive referrals – patient seeks referral
because of family history of affected relative
• Affected relative may live elsewhere in the
country or world
• Proactive referral - GP taking a family history
• Referral suggested by coroner or other health
professional etc.
Approach to referral letters
• Offer an appointment – “opt in” letter; not “choose
and book” – try to offer appointment at convenient
location with appropriate professional (medic or
• Pass the referral to another centre (if out-of-area or
very specialist) or to another service within the
region (e.g. Haematology, Cardiology,
• Reply by letter – often for a family history of cancer
or for carrier testing in “common” autosomal
recessive disorders; sometimes when asking for
genetic testing when such testing may not be
available or not appropriate.
Appointments – urgent vs routine?
Prenatal referrals – treated as urgent
Terminally ill patient – usually cancer
Ward consultation
? Priority – if gene testing result may affect
• Others are generally regarded as routine
Prenatal referrals
• Genetic Counsellor to contact patient and do first
appointment by telephone.
• The date of first contact should be <= 2 days after
referral. The first contact may only be to arrange the
substantive telephone appointment which should be
offered within 5 working days (LWH KPI standard).
• One specific national target for clinical genetic staff is to
provide a prenatal test result to the family within 5
working days of the clinic receiving the laboratory result.
It is expected that services would meet this target 100%
of the time – and indeed much sooner than 5 days.
Genetic testing
• Diagnostic testing
• Carrier testing
• Predictive testing
When referring for carrier testing or
predictive testing
• Provide details of affected relative(s) if you can –
ideally names and dates of birth– and how they
are related to the person you are referring.
• We may know the affected relative (s) – whether
they have had any genetic testing and, if so, if a
mutation was identified.
• If the family have been seen before by us and you
know their family file number please provide it (G
• If you have letters from other centres providing
such information please provide it.
Chromosome abnormalities :
• numerical
• structural
Single gene defects:
• Nuclear genes- autosomal dominant, autosomal
recessive, X-linked recessive and dominant.
• Mitochondrial genes
Multifactorial diseases
Somatic genetic disorders e.g. cancers
Epigenetic disorders – constitutional and in tumours.
Presentation of chromosome
•A child with learning disability
•Child or fetus with multiple congenital
abnormalities / dysmorphism
•Recurrent miscarriage
•Infertility, especially in males
•Chance finding at amniocentesis etc.
Microarray - Overview of Method
Why Implement arrays ?
Advantages of Array CGH
• All 46 chromosomes can be examined in a
single test
• More sensitive and accurate than conventional
• Can reveal specific genes which have been
deleted or duplicated
• May prevent other unnecessary investigations
• May help predict phenotype
• Health Surveillance
Disadvantages of Array CGH
• Will not detect balanced rearrangements.
• May identify “copy number variants” (CNVs) of
uncertain significance (variants of uncertain
significance or “VOUS”)
• Parental analysis required in abnormal cases.
• Some CNVs may have disease associations with
reduced penetrance – susceptibility loci.
• May detect ‘unexpected result’ (“incidental
Prenatal arrays
• Microarray analysis has now being introduced
into prenatal practice
• Arrays are replacing karyotyping for abnormal
• In other situations, at present, we are offering
karyotyping and QfPCR – some other centres
are only offering QfPCR in this situation.
• Known/common mutation or mutational
• Unknown mutation
Molecular Genetic testing
Known mutation
Mutation(s) specific
Point mutations or
copy number changes
Relatively simple
2 week reporting
Unknown mutation
DNA sequencing
Complex analysis
Unclassified variants
8 week reporting
Cheshire & Merseyside Regional Molecular
Genetics Laboratory
Counselling problems in
autosomal dominant diseases
Late or variable age of onset
Reduced penetrance
Variable expression
New mutations
Germ-line mosaicism
If asked questions about autosomal dominant
disorders have a low threshold for referral.
• Hypertrophic
• Dilated
• Others e.g. non-compaction
Inherited rhythm disorders
• Long QT
• Brugada
• Familial heart block
• Short QT (gain of function mutations in 5 K+ channel genes)
Congenital heart disease
Connective Tissue Disorders – with predisposition to aneurysms
Coronary artery disease – monogenic e.g. FH.
• Joint hypermobility is common in childhood,
occurring in 8–39% of school age children.
• 10% population are hypermobile (rheumatology
• Probably not a single condition
• Prevalence depends on age, sex and ethnicity and
decreases with increasing age.
• Girls are generally more hypermobile than boys
and children from Asian backgrounds are
generally more hypermobile than Caucasian
The genetic causes of joint
• Ehlers – Danlos syndromes (EDS)
• Some types of Osteogenesis Imperfecta (OI)
including types I and IV
• Marfan syndrome and related disorders
• Rare HDCT such as pseudoxanthoma elasticum and
cutis laxa syndromes
• A wide range of skeletal dysplasia syndromes eg
pseudoachondroplasia and spondyloepiphyseal
dysplasia congenita
• Developmental syndromes of childhood such as
the Fragile-X syndrome.
Hypermobile EDS
• Diagnosis is clinical
• Brighton criteria for joint hypermobility
syndrome plus skin changes and other conditions
• No gene testing is offered
Genetic service and Hypermobility
• We are a diagnostic service and not a
management service
• Exclude other types of EDS and other diagnoses
• Reassure as thoroughly as possible in relation to
the other types of EDS – esp. vascular EDS –
vascular EDS patients tend not to be that bendy
– hypermobility tends to affect digits mainly in
vascular EDS.
Marfan syndrome
In the absence of family history:
• Aortic Root Dilatation Z score ≥ 2 AND Ectopia Lentis = Marfan syndrome The presence of aortic root dilatation (Z-score ≥ 2 when standardized to age
and body size) or dissection and ectopia lentis allows the unequivocal
diagnosis of Marfan syndrome,
• Aortic Root Dilatation Z score ≥ 2 AND FBN1 = Marfan syndrome - The
presence of aortic root dilatation (Z ≥ 2) or dissection and the identification of
a bona fide FBN1 mutation are sufficient to establish the diagnosis, even when
ectopia lentis is absent.
• Aortic Root Dilatation Z score ≥ 2 AND Systemic Score ≥ 7pts = Marfan
syndrome - Where aortic root dilatation (Z ≥ 2) or dissection is present, but
ectopia lentis is absent and the FBN1 status is either unknown or negative, a
Marfan syndrome diagnosis is confirmed by the presence of sufficient
systemic findings (≥ 7 points, according to a scoring system) confirms the
• Ectopia lentis AND FBN1 with known Aortic Root Dilatation = Marfan
syndrome - In the presence of ectopia lentis, but absence of aortic root
dilatation/dissection, the identification of an FBN1 mutation previously
associated with aortic disease is required before making the diagnosis of
Marfan syndrome.
Counselling problems in autosomal
recessive disease
• Consanguinity
• Heterozygote frequency in different
• Heterozygote detection
Carrier detection in common
autosomal recessive disorders
• Haemoglobinopathies – refer to haematologists
• Cystic fibrosis – 1 in 25 white Caucasians are
• Haemochromatosis – 1 in 8 N Europeans are
• Alpha-1-antitrypsin deficiency – 1 in 25 of N
Europeans are carriers of Z deficiency allele.
Cystic fibrosis
• Current kit tests for 51 mutations
• ? Ethnicity – aimed at European (Jewish, S Europe,
Welsh & Irish) – not Asian mutations
• Pick up rate – in local population 94% gene carriers
will have one of these 51 mutations (if –ve, carrier
risk is reduced to 1 in 410).
• Newborn screening issues – refer “carrier couples”
• Major issue for the lab is telling the lab the names
of affected individuals especially if local (tell them
the mutations if you know them).
HFE gene on chromosome 6
One common mutation C282Y
One “mild mutation” H63D
1 in 200-300 people in the UK will be C282Y homozygotes.
These people are likely to develop biochemical evidence of
increased iron load in adult life, men at an earlier age than
• Studies vary in the frequency of clinical penetrance in C282Y
homozygotes:– 2-38% in men and 1-10% in women .
See van Bokhoven et al. Diagnosis and management of
hereditary haemochromatosis. BMJ 2011; 342: 218-223
• There is no way of predicting which individuals with
biochemical iron overload will go on to develop clinical
disease if untreated.
• With early assessment of genetic risk these complications
can be avoided in ALL patients.
• Homozygotes should have iron studies monitored every 1 yr.
• Occasionally persons who have inherited 1 C282Y mutation
and 1 other “mutation” such as H63D (dual mutation status)
develop clinical signs of HH, particularly if additional risk
factors for iron accumulation are present – e.g. excess
alcohol intake, high iron diet. People with dual mutation
status should have iron studies monitored every 3 years.
• 1 in 8 – 1 in 10 people in the UK will be heterozygotes (gene
carriers) for the common gene mutation (C282Y) - guidelines
have suggested that iron indices be checked every 5 years
Alpha-1 antitrypsin deficiency
• Biochemical phenotyping
• M, S, Z , other rare alleles.
• PI MM. Observed in normal individuals with normal plasma concentration
of AAT who are homozygous for the M allele
• PI MZ. Slightly increased risk for decreased lung function among
• PI SZ. Not usually associated with a high risk for liver or lung disease;
higher risk of developing chronic obstructive pulmonary disease (COPD)
among smokers
• PI ZZ. The onset of respiratory disease in smokers with AATD is between
age 40 and 50 years. In non-smokers, the onset can be delayed to the sixth
decade and is often associated with a normal life span. The overall risk to
an individual with PI ZZ of developing severe liver disease in childhood is
generally low (~2%); the risk is higher among sibs of a child with the PI ZZ
type and liver disease.
• Appropriate to test full siblings of ZZ or SZ
• Testing of other relatives is discretionary - the risk to offspring is most
accurately determined after PI typing of the proband's reproductive
Counselling problems in X-linked
• Carrier detection
• New mutations
• Germ-line mosaicism
If asked questions about X-linked recessive
disorders have a low threshold for referral.
• Main issue is “family history of cancer”
• Issue for doctor is assessing risk
• Issue for patient is “what can be done about
• Screening and prevention issues
• For the clinical geneticist, the additional
question is “can we identify single-gene
subgroups” that are at very high-risk and offer
genetic testing?
Main cancer groups
• Family history of breast cancer and/or ovarian
• Family history of bowel cancer
• Occasional others
Cancer Genetics – basic rules
• More people in the family having had cancer
than we would expect to happen by chance
• Those people having the same or related
• Those cancers occurring at a younger age than
we would expect
• Those cancers occurring in different
generations of the family
Risk groups
• Low risk
• Moderate risk
• High risk
Low risk
• Approximately that of the general population
• No extra screening
• May need emotional support
Moderate risk
Increased risk above that of the general population
Extra screening recommended
Gene testing not appropriate (yet)
Avoid environmental exposures
High risk
At high risk of developing cancer
Extra screening recommended
Gene testing sometimes available
Risk reducing surgery sometimes appropriate
Management of risk groups
• Low risk - Primary Care
• Moderate risk – Secondary Care
• High risk – Clinical Genetics involvement
Breast cancer risk groups
• Lifetime risk for a female is 1 in 8 (12%)
• Low risk group are regarded as those with
estimated lifetime risk < 1 in 6 or 12-17% (i.e.1 1.5 x population risk) – offered national screening
• Moderate risk – estimated lifetime risk of 18-30%
(i.e. 1.5-2.5 x population risk) – offered additional
screening before age 50yrs.
• High risk – estimated lifetime risk >2.5 x
population risk – offered additional screening and
consider gene testing.
Who should be referred ?
Revised NICE guidelines 2013 for familial breast cancer have
been loosened – refer to secondary care if:
• One 1st degree relative with breast cancer under 40 years
• Two 1st degree relatives or one 1st degree and one 2nd
degree relative with breast cancer at any age
• A first-degree relative with bilateral breast cancer where the
first primary was diagnosed at younger than age 50 years
• A first-degree or second-degree relative diagnosed with
breast cancer at any age and one first-degree or seconddegree relative diagnosed with ovarian cancer at any age
(one of these should be a first-degree relative)
• 1st degree male relative with breast cancer at any age
• Three first-degree or second-degree relatives diagnosed
with breast cancer at any age.
Advice should be sought IF:
Any of the following present in the family history but not
fulfilling the above criteria?
• bilateral breast cancer
• male breast cancer
• ovarian cancer
• Jewish ancestry
• sarcoma in a relative younger than 45 years
• glioma or childhood adrenal cortical carcinomas
• complicated patterns of multiple cancers at a young
• paternal history of breast cancer (two or more relatives
on the father's side of the family
Referrals for cancer family history
• If possible provide information about affected
relatives – what cancer(s) and what ages; are
they still alive?
• If possible give information about intervening
relatives who have not had cancer – how old
are they or were they when they died?
• Consider both maternal and paternal families.
Referral to clinical genetics (NICE
guideline 2013)
Direct from primary care if there is a known mutation in
the family e.g. BRCA1, BRCA2.
From secondary care IF
• Two 1st degree or 2nd degree relatives with breast
cancer with an average age before 50 (1 must be 1st
degree relative)
• Three 1st degree or 2nd degree relative with breast
cancer with an average age before 60
• Four relatives with breast cancer at any age
• Various other criteria that include male breast cancer,
bilateral breast cancer and ovarian cancer.
• 2013 NICE guidance - offer genetic testing to a
family member with breast or ovarian cancer if
their combined BRCA1 and BRCA2 mutation carrier
probability is 10% or more.
• 2013 NICE guidance - offer genetic testing in
tertiary care to a person with no personal history of
breast or ovarian cancer if their combined BRCA1
and BRCA2 mutation carrier probability is 10% or
more, when they have a first-degree affected
relative with a carrier probability of 20% in the
family but is unavailable for testing.
• Any woman (?age )with high-grade serous ovarian
Reasons for BRCA testing
Breast cancer patient
• Higher risk of bilateral breast cancer (50% risk)
• Higher risk of ovarian cancer (~50% BRCA1, 20%
• Affects surgical management
• May affect treatment – new tailored drugs - PARP
Ovarian cancer patient
• High risk of breast cancer (80% risk)
• May affect treatment – new tailored drugs - PARP
inhibitors and response to conventional drugs.
A high risk family history of ovarian
• an ovarian cancer predisposing mutation
• 2 cases of ovarian cancer at any age (annual
mammography ≥ 35)
• 1 case of ovarian and 1 of breast cancer both
diagnosed < 50
• 1 case of ovarian and 2 of breast cancer
diagnosed < 60
• 1 case of ovarian and 3 cases of colorectal
cancers, with 1 CRC diagnosed < 50)
Ovarian cancer – what to do ?
• Oral contraception is protective. HRT is not
• Prophylactic bilateral salpingo-oophorectomy
• In BRCA1/2 mutation carriers, BSO < 45 years
decreases the risk of ovarian cancer by 90% and
decreases the risk of breast cancer by up to 50%.
• Women can have can have risk reducing BSO to
reduce their breast cancer risk, including when
they have no increased ovarian risk.
Hormone replacement therapy
• After oophorectomy, women may take HRT (except if
they have had a diagnosis of breast cancer within last 5
• There are few data on HRT in mutation carriers and
pragmatic advice is extrapolated from data in post
menopausal women in the general population.
• The oestrogen only HRT gives a lower risk of breast
cancer compared to combined HRT (oestrogen and
progesterone) but can only be used following TAH and
BSO (oestrogen only HRT is associated with an
increased risk of endometrial cancer).
CRC is common in the UK
• lifetime risk 1 in 25 for men and 1 in 30 for
• 15-20% CRC are familial
• 5-10% due to a primary genetic factor
LYNCH syndrome – modified
Amsterdam criteria
• There should be at least 3 relatives with an Lynch
Syndrome associated cancer (CRC, endometrial,
small bowel, ureter or renal pelvis malignancy)
• One affected relative should be a first-degree
relative of the other two
• At least two successive generations should be
• At least one malignancy should be diagnosed
before age 50 years
• FAP should be excluded in the colorectal cancer
Gene testing
DNA testing of a living affected relative - MLH1,
MSH2, MSH6 (and PMS2)
• If meet Amsterdam criteria
• If nearly meet Amsterdam and there is
endometrial cancer
• If bowel cancer < 50 years
• If affected with a high-mod family history
• Multiple polyps and FAP excluded
If deceased – IHC on tumour sample
Criteria and screening for highmoderate and low-moderate CRC risk
Criteria for high-moderate risk family history CRC Screening
• 3 affected relatives >50
(FDR of each other and
≥ 1 is FDR of proband )
• 2 affected relatives <60
(FDR of each other and
≥ 1 is FDR of proband )
5 yearly colonoscopy 50-75
5 yearly colonoscopy 50-75
Criteria for low-moderate risk family history CRC Screening
• 1 affected FDR < 50
• 2 affected FDR ≥ 60.
One off colonoscopy at 55
One off colonoscopy at 55
Immuno-histochemistry – MLH1
Normal tissue
Normal staining
Tumour tissue
Normal staining
Immuno-histochemistry – MLH1
Normal tissue
Normal staining
HNPCC tumour tissue
Deficient staining
Kathryn’s referral
• Family history of endometrial cancer
• Three first degree relatives
• Wants a hysterectomy
9 years
Died 43 years
Regular check ups
scan and biposy
Ca Womb
CONF age 41 years
Ca Womb
CONF Adenocarcinoma
Clear cell type age 64
Ca Womb 52 years
CONF adenocarcinoma
MSH6 mutation
Mental handicap
Limited understanding
HNPCC genes – MLH1 and MSH2
• Male
– lifetime colon cancer risk of 80%
• Female
– lifetime colon cancer risk of 40-60%
– lifetime endometrial cancer risk of 40-60%
– lifetime ovarian cancer risk of >10%
HNPCC genes – MSH6
• Colon cancer lifetime risk of > 10%
• Endometrial cancer lifetime risk of 70-75%
Gene testing in this family
• Tested MLH1 and MSH2 locally –
• Sent away for MSH6 testing
• Mutation found
How this result affected the proband
• She had requested a hysterectomy as she had
some intermenstrual bleeding
• Cancelled as she had a relapse of her SLE
• Now able to offer her a predictive test
• Help to decide on her treatment options
• She did NOT have the MSH 6 mutation
• She has not had a TAH BSO
• Inter menstrual bleeding stopped
Other effects of this result
• Allow identification of high risk and low risk
family members
• 18 monthly to 2 yearly colonoscopies
• Endometrial screening from 35years
• Risk reducing surgery?
LAST 10 GP referrals seen by me
• 2 sibs dev delay – other sib 15q11.2 del
• FH muscular dystrophy – sister had been seen by us – turned out to
• ? Marfan – anxiety state ; tachycardias ; tall
• Autonomic dysfunction - ?EDS
• ?FAS – I had seen other sibs
• FH mt disorder – gave details of the mutation but not name of
affected family member
• FH gastric cancer in 4 rels – turned out not to be on more
• FH cancer – mother glioblastoms, mat aunt br ca 48; sister
liposarcoma 46
• 6 family members of lady with Brugada SCN5A mutation
• FH ectodermal dysplasia in father; also FH br cancer

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