1. ACMG
Open
Forum
Introduc3on
to
Preliminary
Report
from
Secondary
Findings
in
Clinical
Sequencing
Workgroup
Mike
Watson
March
28,
2012
2. Open
Forum
Agenda
• Introduc)on
– Michael
Watson
• Preliminary
Report
of
the
Secondary
Findings
in
Clinical
Sequencing
Workgroup
– Robert
Green
• Audience
Response
Ques)ons
– Leslie
Biesecker
• Open
Microphone
Discussion
– Michael
Watson
and
Workgroup
Members
Panel
3. Current
College
Ac3vi3es
on
Clinical
Sequencing
• Task
Force
on
WGS/WES
– Co-‐Chaired
by
Sherri
Bale,
PhD
and
David
Miller,
MD
– Informed
ACMG
Board
of
work
for
commiNees
to
pursue
• Posi)on
statement
on
clinical
use
of
WGS/WES
– High
level
statement
from
ACMG
Board
of
Directors
– Dis3nguishes
diagnos3c
component
from
the
screening
component
• Clinical
Laboratory
Standards
for
Next
Genera)on
Sequencing
– Laboratory
Quality
Assurance
CommiNee
workgroup
– Co-‐Chaired
by
Heidi
Rehm,
PhD
and
Pinar
Bayrak-‐Toydemir,
MD,
PhD
• Secondary
Findings
in
Clinical
Sequencing
Workgroup
– This
ad
hoc
workgroup
formed
by
the
ACMG
Board
to
develop
guidelines
– Work
of
many
ACMG
CommiNees
are
dependent
on
addressing
issues
around
the
return
of
secondary
results
4. Secondary
Findings
in
Clinical
Sequencing
Workgroup
• Robert
Green,
MD,
MPH
(Co-‐Chair)
Brigham
&
Women’s;
Harvard
• Leslie
Biesecker,
MD
(Co-‐Chair)
NHGRI/NIH
• Jonathan
Berg,
MD,
PhD
Univ.
of
North
Carolina
• Wayne
Grody,
MD,
PhD
Univ.
Calif.
Los
Angeles
• Bruce
Korf,
MD,
PhD
Univ.
Alabama
Birmingham
• Amy
McGuire,
JD,
PhD
Baylor
• Christa
Mar3n,
PhD
Emory
Univ.
• Robert
Nussbaum,
MD
Univ.
Calif.
San
Francisco
• Julianne
O’Daniel,
MS
Illumina
• Kelly
Ormond,
MS
Stanford
Univ.
• Heidi
Rehm,
PhD
Brigham
&
Women’s;
Harvard
• Marc
Williams,
MD
Geisinger
Health
System
• Sarah
Kalia,
ScM
Brigham
&
Women’s;
(ex
officio)
• Michael
Watson,
MS,
PhD
ACMG
Staff
(ex-‐officio)
(poten0al
COI
were
reviewed
by
ACMG
Board
prior
to
approval)
5. Previous Workgroup
Strategy and Timeline
• Workgroup
chairs
appointed
November,
2011.
• Charge
to
workgroup
ar3culated
by
workgroup
chairs
and
ACMG
Board
of
Directors
in
November/December,
2011.
• Workgroup
members
appointed
and
approved
by
ACMG
Board
of
Directors
in
January,
2012.
• Workgroup
meets
weekly
January-‐March,
2012.
6. Upcoming Workgroup
Strategy and Timeline
• Workgroup
seeks
feedback
from
membership
March-‐
April,
2012.
• Based
upon
feedback,
workgroup
will
revise
approach
and
seek
addi3onal
expert
input
April-‐May,
2012.
• Workgroup
recommenda3ons
will
be
presented
to
ACMG
Board
of
Directors
May,
2012.
• Workgroup
recommenda3ons
will
be
submiNed
for
publica3on
as
ACMG
Guideline
June,
2012.
Concepts
and
ideas
under
considera)on
by
the
workgroup
do
not
yet
represent
ACMG
policy.
7. ACMG
Open
Forum
Preliminary
Report
from
Secondary
Findings
in
Clinical
Sequencing
Workgroup
Robert
Green
March
28,
2012
9. Published
online
March
15,
2012
Also
see
Clinical
PlaAorm
Presenta0on
2
CharloDe
Conv
Center
Ballroom
A-‐D
Friday
4:30
pm,
Abstract
#28
10. Charge
to
the
Workgroup
1. What
principles
should
guide
search
and
repor3ng
of
secondary
findings
from
WES/
WGS?
2. Should
there
be
a
list
of
genes
or
variants
sought,
interpreted
and
reported
on
every
pa3ent
undergoing
WES/WGS?
3. If
so,
what
should
be
on
that
list?
11. An3cipated
Ques3ons
1. Why
the
accelerated
3metable?
2. Who
are
these
guidelines
wriNen
for?
3. Will
these
guidelines
be
“evidence
based”?
4. Is
the
exper3se
of
the
workgroup
members
sufficient?
5. What
is
the
medical
model
for
secondary
findings?
12. What did we NOT address?
• Sequencing
as
screening.
• Dis3nguishing
guidelines
for
adults
vs
children.
• Tes3ng
mul3ple
family
members.
• Considering
ethnicity.
• Obtaining
preferences
from
pa3ents.
• Reanalysis
of
sequence
over
3me.
• Integra3on
of
report
or
sequence
with
medical
records.
• Educa3on
or
qualifica3ons
of
ordering
clinician.
• Patent,
IP,
insurance
or
reimbursement
issues.
13. Charge
to
the
Workgroup
1. What
principles
should
guide
search
and
repor3ng
of
secondary
findings
from
WES/
WGS?
2. Should
there
be
a
list
of
genes
or
variants
sought,
interpreted
and
reported
on
every
pa3ent
undergoing
WES/WGS?
3. If
so,
what
should
be
on
that
list?
14. Principles: initial decisions…
• Guidelines
to
apply
to
molecular
laboratories.
• Leave
educa3on,
counseling,
preference
seing
and
other
contextualiza3on
to
ordering
clinicians.
15. Principles: creating a list…
• Generate
a
specific
list.
• Generate
a
minimum
list
of
variants/condi3ons
that
laboratories
should
look
for
and
return,
recognizing
that
laboratories
may
wish
to
provide
more.
• Revise
the
list
at
least
annually.
16. Principles:
laboratory
transparency…
• Laboratories
genera3ng
WES/WGS
should
have
a
clear
policy
regarding
analysis
and
return
of
secondary
findings.
• This
policy
should
be
stated
clearly
on
laboratory
website,
requisi3on
form,
consent,
and/or
results
report.
• Report
should
include
level
of
coverage
and/or
confidence
for
all
genes
included
on
the
report.
17. Charge
to
the
Workgroup
1. What
principles
should
guide
search
and
repor3ng
of
secondary
findings
from
WES/
WGS?
2. Should
there
be
a
list
of
genes
or
variants
sought
and
interpreted
on
every
pa3ent
undergoing
WES/WGS?
3. If
so,
what
should
be
on
that
list?
18. Principles: creating a minimum list…
• High
penetrance
• Pa3ents
may
be
asymptoma3c
for
a
long
period
of
3me
• Interven3on
clearly
demonstrated
to
be
efficacious
• High
posi3ve
predic3ve
value
• Not
otherwise
detected
by
newborn
screening
19. Principles:
variant
categories…
• Variants
in
ACMG
interpre3ve
categories
1
or
2
are
included
on
this
minimum
list
– Category
1:
Variant
previously
reported
and
a
recognized
cause
of
the
disorder
– Category
2:
Variant
previously
unreported
and
of
the
type
which
is
expected
to
cause
the
disorder
Richards
et
al,
ACMG
recommenda3ons
for
standards
for
interpreta3on
and
repor3ng
of
sequence
varia3ons.
Genet
Med
2008.
20. Were
AR
and
X-‐linked
disorders
considered?
• Homozygotes/compound
heterozygotes
or
hemizygotes
were
considered
separately
for
inclusion
on
the
minimum
list.
• Carriers
were
considered
for
inclusion
only
if
a
carrier
phenotype
has
been
described
– Examples
of
carrier
states
included
on
minimum
list:
Fabry,
Gaucher,
LCHAD
21. Were
NBS
condi3ons
considered?
• Minimum
list
focuses
on
condi3ons
not
detected
rou3nely
on
newborn
screening
panels.
• Some
labs
may
choose
to
report
all
metabolic
disorders.
Ra3onale:
Clinical
sequencing
is
not
an
acceptable
subs3tute
for
NBS.
22. Were
PGx
variants
considered?
• Factors
to
consider:
– Poten3al
for
huge
cost
savings
– Limited
disadvantages
to
returning,
despite
low
penetrance
à Included
(based
on
Pharm
GKB/CPIC)
• However,
need
to
determine
whether
WES
or
WGS
can
accurately
detect
HLA
subtypes
– Abacavir,
Carbamazepine
– Workgroup
will
seek
addi3onal
exper3se
23. Examples
included
on
minimum
list…
• Inherited
cancer
syndromes
and
Marfan
syndrome
– If
a
secondary
finding,
pa3ent
is
unaware
of
risk
and
would
not
otherwise
be
screened
– Poten3al
for
severe
ini3al
presenta3on
• Familial
hypercholesterolemia
– Poten3al
for
severe
ini3al
presenta3on
– Treatments
available
&
effec3ve
• Fabry
– Most
cases
have
late
onset
– ERT
more
effec3ve
if
started
earlier
24. Examples
not
included
on
minimum
list…
• Neurological/Neuromuscular
disorders
– No
interven3on
– Limited
ability
to
detect
repeat
expansions
• Mitochondrial
disorders
– Extremely
variable
presenta3on
• Inherited
thrombophilia
variants
– Low
PPV
• APOE
– Low
penetrance
– No
interven3on
25. Examples
that
were
challenging…
• Hypertrophic
cardiomyopathy
– Long
asymptoma3c
period
– Poten3al
for
severe
ini3al
presenta3on
– Low
PPV
for
some
variants
and
unclear
penetrance
– Knowledge
carries
high
burden
à
Included
• Bio3nidase
deficiency
– Simple
treatment
– Unclear
meaning
in
an
asymptoma3c
pa3ent
à
Not
included
26. Limita3ons
of
these
dran
guidelines…
• Current
technological
capabili3es
of
WES/
WGS.
• Point
muta3ons
and
in/dels,
not
CNVs.
• Decision
to
return
variants
for
certain
condi3ons
may
depend
on
age
of
pa3ent
(especially
children
<
age
2).
27. Charge
to
the
Workgroup
1. What
principles
should
guide
search
and
repor3ng
of
secondary
findings
from
WES/
WGS?
2. Should
there
be
a
list
of
genes
or
variants
sought
and
interpreted
on
every
pa3ent
undergoing
WES/WGS?
3. If
so,
what
should
be
on
that
list?
28. ACMG
Open
Forum
Audience
Response
Ques3ons
Related
to
the
Secondary
Findings
in
Clinical
Sequencing
Workgroup
Leslie
Biesecker
March
28,
2012
