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A homozygous NOTCH3 mutation p.R544C and a heterozygous TREX1 variant p.C99MfsX3 in a family with hereditary small vessel disease of the brain.
[cadasil]
Mutations
in
the
TREX
1
and
NOTCH
3
genes
cause
retinal
vasculopathy
with
cerebral
leukodystrophy
(
RVCL
)
and
cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leukoencephalopathy
(
CADASIL
)
,
respectively
.
Both
are
hereditary
small
vessel
diseases
of
the
brain
(
HSVDB
)
.
We
performed
mutational
analyses
of
TREX
1
in
genomic
DNA
from
39
unrelated
patients
who
were
NOTCH
3
-
negative
in
genetic
testing
,
selected
out
of
72
unrelated
consecutive
patients
with
HSVDB
.
Only
one
patient
had
a
TREX
1
sequence
variation
,
a
heterozygous
TREX
1
c
.
294
dupA
,
putatively
resulting
in
a
truncated
protein
,
p
.
C
9
9
MfsX
3
.
The
medical
history
of
the
patient
's
family
was
scrutinized
,
which
revealed
that
heterozygous
TREX
1
p
.
C
9
9
MfsX
3
was
not
segregating
with
the
HSVDB
.
Re-examination
of
the
NOTCH
3
sequence
data
of
the
proband
led
to
the
identification
of
a
homozygous
NOTCH
3
c
.
1630
C
>
T
(
p
.
R
544
C
)
mutation
,
which
segregated
with
the
HSVDB
in
the
family
.
The
proband
had
a
slightly
more
severe
phenotype
in
comparison
with
her
heterozygous
p
.
R
544
C
sister
.
TREX
1
mutation
is
not
a
common
cause
of
HSVDB
.
TREX
1
p
.
C
9
9
MfsX
3
is
not
a
dominant
mutation
.
Homozygosity
of
the
NOTCH
3
p
.
R
544
C
has
a
modestly
deleterious
effect
on
the
CADASIL
phenotype
.
The
NOTCH
3
mutation
may
cause
CADASIL
through
a
gain-of-toxic
function
effect
,
which
can
be
modified
by
other
genetic
or
environmental
factors
and
results
in
the
phenotypic
variation
of
CADASIL
.
Diseases
Validation
Diseases presenting
"p.r544c sister.trex1 mutation"
symptom
cadasil
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