Rare Disease Day 2017 March 30 - 31, 2017 Day 2: Genomics for Rare Diseases Dr. Anna Lehman Provincial Medical Genetics Program Adult Metabolic Diseases Clinic Department of Medical Genetics BC Children’s Hospital Research Institute
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RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
1. Genomics
for
Rare
Diseases
Dr.
Anna
Lehman
Provincial
Medical
Genetics
Program
Adult
Metabolic
Diseases
Clinic
Department
of
Medical
Genetics
BC
Children’s
Hospital
Research
Institute
2. Definitions
• Rare
Disease:
affecting
fewer
than
1
in
2000
people
• Mendelian
disease:
simple,
predictable
genetics
3. Not
all
Mendelian
diseases
are
Rare
• Familial
Hypercholesterolemia
(1
in
500)
Austin,
Am
J
Epidemiol
2004;160:407–420
• Familial
Cardiomyopathies
(Hypertrophic: 1
in
500;
Dilated: 1
in
500)
Gene
Reviews
• Hereditary
Cancer
(HBOC:
1
in
400;
Lynch
1
in
440)
Gene
Reviews,
2017
• Nonsyndromic Intellectual
Disability
(~
1
in
100)
my
estimate
4. Not
all
rare
diseases
are
Mendelian
• Polymyositis
(prevalence
1
in
14,000)
• Childhood
leukemia
(incidence
1
in
20,000)
• Congenital
diaphragmatic
hernia
(incidence
1
in
2500)
5. Rare
Diseases
are
Common
• 1
in
3
children
admitted
to
BCCH
have
a
rare
genetic
disease.
• More
than
1,500
rare
diseases
do
not
have
a
known
cause.
• Too
often,
children
and
families
affected
by
rare
diseases
must
undertake
a
frustrating,
time-‐consuming,
expensive
and
painful
journey
in
search
for
a
diagnosis
– the
“diagnostic
odyssey”.
7. January
7th,
2017 4,919confirmed
genetic
disorders
(phenotype
and
known
gene)
Heterogeneic disorders
are
broken
down
into
subtypes
for
each
different
gene
Growing
focus
on
genetic
subtypes,
because
many
new
therapies
are
gene-‐specific,
or
even
mutation
specific
8. Retinitis
Pigmentosa
An
endpoint
disease
resulting
from
many
different
molecular
mechanisms
National
Eye
Institute
67
genes
responsible
and
counting
(RetNet)
1
in
3500
prevalence
Genetic
diagnostic
rate
2010:
50%
(Berger
et
al
2010)
Genetic
diagnostic
rate
2015:
65%
12. Panel
or
Exome?
• Previously,
panels
had
a
major
advantage
of
allowing
virtually
complete
sequencing
coverage
of
all
exons
(usually).
• Now,
a
high-‐end
exome
can
provide
similar
coverage.
• So
main
reason
to
rely
on
panels
as
much
as
possible
is
cost.
• A
panel
$1
– 3K
and
a
trio
exome
is
$6K
– 11K
• Second
reason
to
use
panel
is
to
avoid
VUS
and
IFs
13. When
to
order
an
exome
• Very
broad
differential
(eg.,
intellectual
disability
/
developmental
delay)
• “Weird”
presentation
(maybe
more
than
one
diagnosis)
• You
need
a
1
week
turn
around
time
• You
won’t
be
satisfied
by
a
negative
result-‐-‐-‐you
want
to
discover
novel
genes
in
the
sequence
data
yourself
• Disease
discovery
pace
is
so
fast
right
now,
your
disease
panel
will
be
outdated
in
a
year.
15. 651 kids
considered
for
exome
sequencing
401 approved
(total
will
be
500)
107 exomes
complete
56 diagnoses
made
(52%)
28 have
mutations
in
new
candidate
genes
• Fewer
invasive
tests
• More
effective
therapy
• Anticipatory
screening
51
kids
remain
undiagnosed
CAUSES
Clinic
as
of
September
2016
16. • Two
siblings
not
growing
well
&
behind
in
development
• Both
had
abnormal
urine
biochemical
profile
with
results
suggestive
of
beta
ureidopropionase deficiency
– but
sequencing
of
UPB1
gene
– negative
– del/dup
negative
• MRI
– nonspecific
ventriculomegaly
• Chromosomal
microarray
normal
16
17. Sibling
wt: 74
v: 45
TKT
(transketolase)
NM_001135055.2:c.1690_1692delTAT
NP_001128527.1:p.Tyr564del
autosomal recessive = compound heterozygous
Child
wt: 73
v: 43
Mother
wt: 52
v: 62
SHORT STATURE,
DEVELOPMENTAL DELAY, AND
CONGENITAL HEART DEFECTS
• developmental delay
• global developmental delay
• microcephaly
Child’s phenotypeDisease phenotype
Father
wt: 120
v: 0
Functional impact
• PROVEAN Genome Variants
Result (human37_66) prediction
is deleterious
• This variant results in a single
amino acid deletion 564 of 623
in exon 13 of 15.
Population frequency
• 0 in-house
• In ExAC
• 6/121,242 alleles
• 0 homozygous
• African >MAF=9.612e-05
• Not in DECIPHER or LOVD
18. Sibling
wt: 84
v: 70
TKT
(transketolase)
NM_001135055:exon9:c.1202G>A:p.R401H
autosomal recessive = compound heterozygous
Child
wt: 82
v: 55
Mother
wt: 126
v: 0
SHORT STATURE,
DEVELOPMENTAL DELAY, AND
CONGENITAL HEART DEFECTS
• developmental delay
• global developmental delay
• microcephaly
Child’s phenotypeDisease phenotype
Father
wt: 61
v: 66 Functional impact
• 4/4 in silico programs predict an
impact
• CADD=35
Population frequency
• 0 in-house
• Not in dbSNP, EVS, or ExAC
• Not in DECIPHER or LOVD
21. How
much
evidence
is
needed
for
a
gene
to
be
included
in
the
clinome?
• One
published
patient?
• Ten
patients
in
a
database?
• A
mouse?
• A
Western
blot?
• A
luciferase
assay?
• An
odds
ratio?
21
What
if
it
is
only
a
susceptibility
gene?
22. The
Deciphering
Developmental
Disorders
Study
• 1,133
children
with
severe,
undiagnosed
developmental
disorders,
and
their
parents,
underwent
a
combination
of
exome
sequencing and
microarray
• As
of
December
2014,
a
genetic
cause
had
been
found
for
31%
• The
study
went
on
to
recruit
14,000
probands
Nature 519, 223–228,
2015
38. Or,
alt.
title:
“75
million
new
dbSNP entries,
and
time
for
an
Hg
update”
40. Resolving
a
VUS
1. Decide
if
segregation
studies
in
your
family
will
be
meaningfully
helpful.
Of
course,
for
many
conditions
with
incomplete
penetrance,
you’re
really
only
wanting
to
test
clearly
affecteds.
2. Consider
doing
parents
(determine
if
cis or
trans
for
AR;
de
novo
for
AD)
3. Consider
functional
studies
4. Wait
and
re-‐visit
the
literature