Transcript Genetic Counselling

Genomic Counselling
Alison M. Elliott, PhD, MS, CGC
Nasim Monfared MSc, CGC
Outline
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Consenting/Guidelines/Checklist/Challenges
Incidental Findings
Research in CAUSES/RAPIDOMICS
SickKids genome clinics: Lessons learned
(consent, analysis, disclosure)
• Adolescnet experience with genome
sequencing
• Cases
CAUSES - TREATING OUR FAMILIES
Referral sent with relevant clinical information
Genomics Consultation
Alternate Advice for
testing
Research Visit
Genetic Counselling
Physical Examination
Consult letter sent to referring MD
Sequencing & bioinfomatics
Diagnosis
Clinical Interpretation with
CAUSES team and referring
MD
No Diagnosis
Sanger
validation –
clinical
report
Follow-up with family
Genetic Counselling
New management plan
Follow-up with family
Genetic Counselling
Revisit genomic
data
Eligible for other
research
Informed consent-minimal
requirements (Darilek et al., Genet Med 2008)
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Description – of test process
Benefit – that is expected
Risk – possible disadvantages, risks, complications
Voluntary- voluntary nature
Refusal – at any time without consequences
Alternative test – if available
Confidentiality – measures to ensure, privacy
Future Use – destination and further use - research
Incidental Findings –management and right not to
know
The advantages of a Checklist
• Ensures information covered for gc
• Ensures consistency amongst different
genetic counsellors involved in clinic
• Basic messaging is the same
Basic Genetics
 use cookbook analogy (book=genome,
chapter/course=chromosome, recipe=gene,
ingredient=DNA base)
 genetic variation is the norm, not the exception
 already tested a few genes, now want to take a
more unbiased approach
GWS
 explain technology – GWS and then analyzing
variants
 we will be sequencing child and parents but only
“testing” the child; parents used mainly to
validate findings
 types of results possible (pathogenic, benign,
VUS) – about 25% chance of finding an answer
 current limitations of technology – “most
sequence information obtained will be of
unknown meaning and importance”
GWS
 diagnostic findings - list of variants
related to primary diagnosis
 validation of top 2-3 of these variants
(ie. confirmation on patient and/or
parents) - primary findings will be
replicated in a clinical lab by Sanger
Incidental Findings
 how we might find them “accidentally”, unlikely
but possible through the approach used in this
study
 give an example (i.e. BRCA1 gene mutation)
 option to know or not to know: adult onset
actionable conditions
 what will be reported : childhood onset,
medically actionable, e.g. retinoblastoma
 what will not be reported: unexpected family
relationships, ancestry, non-actionable findings
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Implications of Findings
 getting information- for themselves, for siblings, for
extended family
 treatment or surveillance options – i.e. diet, medication,
surveillance
 telling friends/family – impact on other family members
 life/disability insurance and employment- lack of GINA in
Canada S-201 (May 2016)
 medical records – child results reported to clinical chart
and/or family doctor
 IFs: for parents go back to them and they decide what to
do
Other consent forms
 Biobank – future research
 Photography
 DECIPHER – only causative results will be
included
Additional Information
 health economics study – first Q after initial
visit and 2nd Q 6 months post-results
 DECIDE Usability study – depending on
randomization
 sample storage
 data reanalysis every 6 months
 research opportunities: if GWS does not
identify anything OR if we find something
that is not diagnostic but is causative
Timelines
 should have sequencing results in 3-4
months ONCE it starts, but analysis time
can vary – (depending on whether centre is
batching samples)
 primary diagnosis results will be returned
first; IFs second (depending on findings)
 we will stay in touch but they can call and
ask at any time
Review of Results
 Results will be sent to treating physician
 Treating physician will contact family
directly to book an appointment for
results discussion and coordinate with
genetic counsellor
 GC will be involved for follow-up
counselling
Challenges
• Research Ethic Board requirements
• Consent forms should be patient friendly
• When does consent become uninformed –
length of consent form
• Protocols differ from centre to centre
• Our consent form is currently 14 pages –
different form for each parent and proband
• Time with patient – send consents ahead of
appt
Consent for GWS
(Burke and Clarke, Arch Dis Child 2016)
• Family history – consider potential known or
likely genetic disease
• Describe method being used
• Broad description of categories of results –
pathogenic, benign, incidental findings,
variants of unknown significance
Consent for GWS
(Burke and Clarke, Arch Dis Child 2016)
• Potential need for biological parental samples
to understand implication of variant
• Potential future recontact as genetic
knowledge and understanding improves
• Use of structured consent forms and
information leaflets and resources to support
information sharing and decision-making
Incidental Findings
• Findings (variants) unrelated to primary
diagnosis
• Pathogenic variants that could alert patients
and providers to important medical
conditions not previously suspected in the
individual
CCMG guidelines
• “until the benefits of reporting incidental
findings are established, we do not endorse
the intentional clinical analysis of diseaseassociated genes other than those linked to
the primary diagnosis” (CCMG position
statement, Boycott et al., 2015)
• CAUSES - not specifically screening for
incidental findings, parents DNA used to assist
in the analysis of child’s test
So how do we handle them?
• CAUSES – pediatric onset medically
actionable will be reported
• Adult – adult-onset medically actionable –
opt in or opt out
• “Actionable” indicates the availability of a
therapy that credible scientific evidence
indicates can significantly reduce the
mortality or morbidity of disease
CAUSES Clinic
Consenting
• 1) The primary goal of this study to
identify the variants in a patient’s
DNA that cause the genetic disorder.
This goal will be accomplished by
using GWS.
• 2) The second goal is to study the
healthcare costs associated with having
a suspected genetic disorder. This goal
will be accomplished by performing a
comprehensive healthcare economic
analysis that will involve reviewing
healthcare records and related data
resources.
• 3) We will also be studying the
effectiveness of an online
educational tool to assist in the
families’ decision making process.
Options
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Photography
Incidental findings (parent)
Future Research
Biobanking (proband)
DECIPHER
The consenting process
• Families will be counselled that we are not
specifically screening for incidental findings in
the child and that the parents’ DNA will be
used to assist in analysis of the child’s test
and not to screen for other disease-related
variants.
• Non-paternity will not be disclosed.
• Regarding children (and incompetent adults),
the parents / guardian will be informed that
pathogenic incidental findings will be
reported back for actionable disorders that
may have childhood onset of symptoms.
Examples include disorders such as:
Neurofibromatosis Type 1, BeckwithWeidemann, Long QT syndrome.
• The parents/guardian will be informed that
we will not disclose the status of exclusively
adult-onset risk alleles in children.
• Adult participants will be given the option for
receipt of pathogenic incidental findings
related to medically actionable conditions.
“Actionable” for our purposes indicates the
availability of a therapy that credible scientific
evidence indicates can significantly reduce
the mortality of morbidity of a disease.
What about carrier status?
• One possible special scenario is the
finding of an X-linked recessive mutation
in a carrier mother. Actionability in this
scenario would relate to a 25% risk of a
pregnancy being affected, which may
meaningfully alter pregnancy planning.
Carriers and IFs
• In contrast, finding that only one
parent is a carrier of an autosomal
recessive condition would not
dramatically increase risk of having
an affected child, and this would not
be reported back as an actionable
incidental finding.
What gets reported out?
• Analytical validity – Sanger post GWS
• Clinical Significance – clinical correlate
• Actionability – potential to modify disease
course
• Importance of having everyone at the table at
time of variant discussion:
Referring/treating physician, bioinformatician,
molecular geneticists, clinical research team –
geneticists, subspecialists and genetic
counsellors
When we do not have a variant
to Sanger:
•Follow up with family – coordinated by
treating physician
•CAUSES Genetic counsellor involved
•Revisit genomic data in six months
Research – CAUSES and
RAPIDOMICS
• Comparing parental attitudes and
motivations to pursue sequencing in pediatric
versus NICU populations
• Questions
• Comparing uptake of sequencing
• Comparing uptake of IFs
Initial phone contact with GC; GC emails consent forms
Knowledge; Decisional Conflict (DCS)
Full GC via Video
Conferencing
•SURE
•Knowledge
•DCS
DECIDE
Info Sheet
•Knowledge
•DCS
•SURE
•Knowledge
•DCS
(exclusions)
Genetic
Counselling
Genetic
Counselling
•SURE
•Knowledge
•DCS
•SURE
•Knowledge
•DCS
Additional genetic counselling to address questions prn; update family
history; complete the checklist; sign consents; clinical exam; blood draw
Usability Feedback &
Health Economics
RESULTS
Knowledge; Decisional Regret;
Values Slider & Health
Economics
Why families need DECIDE
Enable families to gain the knowledge they
need to make the choices right for them
When patients use decision aids, they:
Improve knowledge of options
More accurate expectations
More informed decision making
Decisions more in keeping with values
Less decisional regret
Why physicians need DECIDE
Allow all physicians to ensure their patients
are informed
Web-based platform for counselling can be:
More accessible
More effective
Less expensive and
Equally acceptable
Will make the test more universally
accessible
Economic Evaluation
Survey
• Completed by primary caregiver
• Wave 1: Initial email sent approximately 2 weeks
after intake appointment
• Wave 2: Initial email sent approximately 6
months after results are shared with the family
Economic Evaluation
Survey
• Parental Quality of Life
– Caregiver Burden
– Anxiety (GAD-7) & Depression (PHQ-8)
– Attitudes towards obtaining a causal diagnosis
• Healthcare Resource Utilization by child in the past 6 months
– Inpatient hospital stays
– ER visits
– Outpatient procedures/tests
– Visits to BC Children’s Hospital
– Visits to other specialist physicians
– Visits to family doctor
– Visits to allied health professionals
• Other costs for family & society
–Transportation costs
–Caregiver costs
–Schooling costs
–Productivity costs (employment,
absenteeism, presenteeism)
Lifetime Health Care
Costs
• Patient Charts & PHSA data
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Specialist consultations at BCCH
ER visits & ICU stays at BCCH
Surgeries and other procedures at BCCH
Diagnostic imaging (province-wide)
Laboratory tests (province-wide)
• PopData BC
– General practitioner & non-BCCH specialist visits
– Prescription medications
– Hospitalizations
Transition to Nasim
SickKids genome clinic workflow
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End of one journey, beginning of
another
Pre-test counselling
and education
-What is test
-For whom
-What can you expect
-What would a result
mean
-When will you know
-What happens after
Post-test counselling
and education
ES/GS
-Decisional
conflict
-Questions/
concerns
Clinical or research
report
-What is the result
-For whom
-What does the
result mean
-What happens now
Non-genetics
specialists
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Common misconceptions &
frequent questions
Actionability of research results –
beginning of a journey
Making sense of VUSs
In my mind she can’t make this
decision, she is only 14!
What about my risk information
Research
vs. clinical
results
VUS
Index or
trio
Consent/
assent
What and when
information is
disclosed
Why is it taking so long?
Maybe there is something
we can do to treat him
So, it’s not genetic!
What do you mean you didn’t find
anything? He has something!
Hopes &
limitations
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Secondary findings: public
sentiment vs. policy
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Do you really want to know?
Michele Gornick, Erica Sutton, Nicole Exe, Kerry Ryan, Aaron Scherer, Wendy Uhlmann,
J. Scott Roberts, Scott Kim, Raymond De Vries (ACMG meeting 2015)
Full day deliberative democracy session:
- Education session and small group discussions
- Reconsideration of desire to learn all results of genome sequencing.
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Some change their mind
Upon return of primary results choices regarding adult
medically actionable variants were confirmed
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Some change their mind
Upon return of primary results choices regarding adult
medically actionable variants were confirmed
Yes to No
Undecided
to No
No to Yes
Undecided
to Yes
Undecided
4
7
5
1
4
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No primary diagnosis but….
• Psychological impact of a “new problem”
• Not clear if parents/participants are affected
differently by this information
Primary finding
+
+
-
-
Secondary finding
+
-
+
-
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Do you really want to know?
Participant
Age
Sex
Medical Condition
Decision re: SF
Ethnicity
1A
16
M
Achromotopsia
All, except carrier
status
Caucasian
2A
16
M
Macular Dystrophy
All
Caucasian
3A
19
F
Van Hippel Lindau
None
Iranian
4A
17
F
Ehlers Danlos
Syndrome
All
Caucasian
5A
18
F
Ehlers Danlos
Syndrome
All
Caucasian
6A
17
F
Ehlers Danlos
Syndrome
All
Caucasian
7A
13
F
Bicsupid aortic valve
stenosis
All
Canadian/aboriginal/Eng
lish/Newfoundland
8A
19
M
Ocular albinism
All
Caucasian/Scottish
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Preliminary results
1. Familial factors for knowing SF
– Adoption
– Family history
– Parental discussion
2. Personal health history and status for knowing SF
– Effect that secondary findings may have on primary condition
– Effect that primary condition has on knowing secondary findings
3. Perceived value and weight of knowledge of SF
– Value of the information
– Weight of the decisions
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Familial Factors
• Adoption
“It was more not knowing, my mum’s adopted, so not knowing our
genetic background from that side…was more of the motivation to
look at it and sign off that, yes I wanted to learn about secondary
findings because that’s murky waters and she doesn’t know.”
- Participant 6A, chose to know SF
Familial Factors
• Family History
“Like, we don’t have a family history of any untreatable, like Huntington’s
disease or anything like that, so I wasn’t really worried about anything like
that.”
- Participant 3A, chose not to know SF
“I think looking for specific cancers and stuff that have occurred in my dad’s
side of the family, like lung cancers and other, my mum had skin cancer, just
looking for other stuff that has appeared in my relatives’ later years that I, if
I had known earlier than they could then maybe there could be something
that I could do different than they did.”
- Participant 6A, chose to know SF
Familial Factors
• Parental discussion
“My father and step-mother were both really supportive of
what I chose. They said, honestly, like, do whatever you want;
do whatever your comfortable with. But my mom really, like, I
think she was more interested in the science honestly… and,
and, and I guess also the, like, potential of early treatment and
early diagnosis so she was really pushing for me to do it”
- Participant 3A, chose to
not know SF
Personal Health Factors
• Effect that secondary findings may have on primary condition
“I think [my condition] has influenced my decisions cause with my
eyesight, and then learning other things that could happen, [there
are] a lot of diseases that are tied to it. My main disease is my
eyesight and then a lot of different diseases, like another disability,
can worsen can worsen my eyesight”
- Participant 6A, chose to know all SF
Personal Health Factors
• Effect that primary condition has on knowing secondary
findings
“I think that given the circumstances, I was; like, I chose not to know
anything because I didn’t want to know about any cancer. Basically
since I’d already gone through that scare once so I just didn’t want to
go through it again.”
- Participant 3A, chose not to know about SF
Knowledge of Secondary Findings
• Weight of the decision
“Because, like, mainly the, the things I was doing day-to-day were
immediate decisions, they would have immediate, like, repercussions
or outcomes or whatever, right? But this was for the rest of my life…”
- Participant 3A, chose not to know SF
“That’s a good question. Nothing, like, really affects me… It’s just I
don’t really think about it a lot…. It wasn’t difficult to make the
decision. I thought it was pretty easy.”
- Participant 2A, chose to know all SF
Summary of Findings
• Preliminary results suggest that adolescents who are
capable of understanding and appreciating SF include a
number of factors in their decision to learn of SF including
familial and personal health factors
• Adolescents also take into consideration the value, weight
and impact of the knowledge, including preparation for
future, guiding medical management, prevention of disease
• Results suggest that although some adolescents did not find
stress in the decision, others took more time to make the
decision and the process for some was stressful
Acknowledgments
• Sarah Bowdin
• Steve Meyn
• Cheryl Shuman
• Christian Marshall
• James Stavropolous
• Raveen Basran
• Robin Haymees
• Peter Ray
• Randi Zlotnik Shaul
•
•
•
•
•
•
Michael Szego
James Anderson
Robyn Byrne
Ronni Cohn
Chris Carew
Adel Gilbert
Patients and families
Centre for Genetic Medicine
SickKids
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Case
• Child is referred for intellectual disability, cleft
lip, agenesis of one kidney, esotropia
• Investigations – uninformative
• No variant identified related to primary
diagnosis
• Sequencing reveals a VUS in SCN5A shared by
a parent
• Now what?
Case
• Severe developmental delay
• Progressive microcephaly
• Compound heterozygote - MCM3AP
• In silico predictions suggest both variants are
damaging
• Association with human disorder – not
confirmed
Grey zone: phenotype
SQSTM1: c.C1175T (p.Pro392Leu)
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Grey zone: phenotype
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So, what is the diagnosis?
8 year old with febrile episodes, possible
underlying movement disorder, hypotonia,
developmental regression especially motor
(had normal development in first year of
life)
ATP1A3 Complex phenotype with two genetic disorders:
- ATP1A3 pathogenic variant associated with CAPOS Syndrome
explains episodic hypotonia and regression history.
- 2p16.3 337-kb pathogenic deletion overlapping NRXN1 gene
associated with global developmental delay and Autism Spectrum
disorder.
De novo
De novo
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So, what is the diagnosis?
Multiple parenchymal cavernomas, developmental
delay and hydrocephalus
CCM2
Complex phenotype with two genetic disorders:
- CCM2 pathogenic variant related to Cerebral cavernous
malformation (CCM) diagnosis. Potential pharmacotherapy
interventions for CCM.
Paternally
inherited
- 8q22.1 1.16-Mb pathogenic deletion.
De novo
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And how is this inherited?
cavernous
hemangioma
diagnosed in his 50's
Cerebellar
cavernoma,
migraine and
vertigo
18 year old with multiple
parenchymal cavernomas,
developmental delay and
hydrocephalus
CCM2
Complex phenotype with two genetic disorders:
- CCM2 pathogenic variant related to Cerebral cavernous
malformation (CCM) diagnosis. Potential pharmacotherapy
interventions for CCM.
Paternally
inherited
- 8q22.1 1.16-Mb pathogenic deletion.
De novo
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“I was hoping for an answer but not
this”
OMIM - PKAN - Neurodegeneration with brain iron
accumulation
Clinically classified into classic, atypical, and
intermediate phenotypes:
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Classic: onset in first decade, rapid progression, loss
of independent ambulation within 15 years
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Atypical: onset in second decade, slow progression,
maintenance of independent ambulation up to 40
years later
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Symptomatic @4
years
Intermediate: onset in first decade with slow
progression or onset in second decade with rapid
progression
70
“this is such a relief”
OMIM – LARP7 Alazami syndrome
Clinical Features
Alazami et al. (2012) described a large consanguineous family from the
Southern Province in Saudi Arabia in which 10 children among 3 interrelated
branches had facial dysmorphism, severe intellectual disability, and
primordial dwarfism. All patients had growth parameters 3.5 SD below the
mean. Some patients had nonspecific and inconsistent skeletal findings, for
example, scoliosis and mild epiphyseal changes in the proximal phalanges,
but no frank dysplasia and a bone age consistent with chronological age.
Consistent dysmorphic features included malar hypoplasia, deep-set eyes,
broad nose, short philtrum, and macrostomia. Laboratory investigation
revealed normal plasma amino acids and acylcarnitines, urine organic acids,
very long-chain fatty acids, CBC, renal profile, and bone profile. MRI, which
was performed on 2 patients, was largely unremarkable in one and showed
unilateral mild insular and anterior frontal gyrus cortical thickening in the
other.
8yr
Developmental
Delay, Short
Stature,
Metaphyseal
Dystplasia
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A VUS is a VUS is a VUS?
Variant of uncertain significance
Pathogenic
Benign
Trending
benign
Unknown
significance
Trending
pathogenic
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Grey zone: this is a VUS but….
cavernous hemangioma
diagnosed in his 50's
18 year old with multiple
parenchymal cavernomas,
developmental delay and
hydrocephalus
Cerebellar cavernoma,
migraine and vertigo
Primary finding:
CCM2 pathogenic variant
8q22.1 pathogenic deletion
Secondary finding:
RYR2 variant
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Another example
•
RYR2:c.3320C>T(p.Thr1107Met)
Evidence:
• Rare 0.04% ExAC
• Conserved in primates
• Associated with HCM in 1 family, segregated in 4 affected family members and at
least 1 case report of tachycardia but seen with a KCNH2 variant
• One study report of functional abnormality
• Sift path, Polyphen tolerant.
• ClinVar: Partners VUS, GeneDx Likely benign
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A VUS is a VUS is a VUS?
Variant of uncertain significance
Pathogenic
Benign
Trending
benign
Unknown
significance
Trending
pathogenic
75