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Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease.
[holt-oram syndrome]
Recent
studies
have
identified
the
genetic
underpinnings
of
a
growing
number
of
diseases
through
targeted
exome
sequencing
.
However
,
this
strategy
ignores
the
large
component
of
the
genome
that
does
not
code
for
proteins
,
but
is
nonetheless
biologically
functional
.
To
address
the
possible
involvement
of
regulatory
variation
in
congenital
heart
diseases
(
CHDs
)
,
we
searched
for
regulatory
mutations
impacting
the
activity
of
TBX
5
,
a
dosage-dependent
transcription
factor
with
well-defined
roles
in
the
heart
and
limb
development
that
has
been
associated
with
the
Holt-
Oram
syndrome
(
heart
-
hand
syndrome
)
,
a
condition
that
affects
1
/
100
000
newborns
.
Using
a
combination
of
genomics
,
bioinformatics
and
mouse
genetic
engineering
,
we
scanned
∼
700
kb
of
the
TBX
5
locus
in
search
of
cis-regulatory
elements
.
We
uncovered
three
enhancers
that
collectively
recapitulate
the
endogenous
expression
pattern
of
TBX
5
in
the
developing
heart
.
We
re
-sequenced
these
enhancer
elements
in
a
cohort
of
non-syndromic
patients
with
isolated
atrial
and
/
or
ventricular
septal
defects
,
the
predominant
cardiac
defects
of
the
Holt-
Oram
syndrome
,
and
identified
a
patient
with
a
homozygous
mutation
in
an
enhancer
∼
90
kb
downstream
of
TBX
5
.
Notably
,
we
demonstrate
that
this
single
-base-pair
mutation
abrogates
the
ability
of
the
enhancer
to
drive
expression
within
the
heart
in
vivo
using
both
mouse
and
zebrafish
transgenic
models
.
Given
the
population-
wide
frequency
of
this
variant
,
we
estimate
that
1
/
100
000
individuals
would
be
homozygous
for
this
variant
,
highlighting
that
a
significant
number
of
CHD
associated
with
TBX
5
dysfunction
might
arise
from
non-coding
mutations
in
TBX
5
heart
enhancers
,
effectively
decoupling
the
heart
and
hand
phenotypes
of
the
Holt-
Oram
syndrome
.
Diseases
Validation
Diseases presenting
"heart diseases"
symptom
22q11.2 deletion syndrome
alpha-thalassemia
holt-oram syndrome
systemic capillary leak syndrome
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