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Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1.
[primary hyperoxaluria type 1]
Definitive
diagnosis
of
primary
hyperoxaluria
type
1
(
PH
1
)
requires
analysis
of
alanine
:
glyoxylate
aminotransferase
(
AGT
)
activity
in
the
liver
.
We
have
previously
shown
that
targeted
screening
for
the
3
most
common
mutations
in
the
AGXT
gene
(
c
.
33
_
34
insC
,
c
.
508
G
>
A
,
and
c
.
731
T
>
C
)
can
provide
a
molecular
diagnosis
in
34
.
5
%
of
PH
1
patients
,
eliminating
the
need
for
a
liver
biopsy
.
Having
reviewed
the
distribution
of
all
AGXT
mutations
,
we
have
evaluated
a
diagnostic
strategy
that
uses
selected
exon
sequencing
for
the
molecular
diagnosis
of
PH
1
.
We
sequenced
exons
1
,
4
,
and
7
for
300
biopsy-confirmed
PH
1
patients
and
expressed
the
identified
missense
mutations
in
vitro
.
Our
identification
of
at
least
1
mutation
in
224
patients
(
75
%
)
and
2
mutations
in
149
patients
increased
the
diagnostic
sensitivity
to
50
%
.
We
detected
29
kinds
of
sequence
changes
,
15
of
which
were
novel
.
Four
of
these
mutations
were
in
exon
1
(
c
.
2
_
3
delinsAT
,
c
.
30
_
32
delCC
,
c
.
122
G
>
A
,
c
.
126
delG
)
,
7
were
in
exon
4
(
c
.
447
_
454
delGCTGCTGT
,
c
.
449
T
>
C
,
c
.
473
C
>
T
,
c
.
481
G
>
A
,
c
.
481
G
>
T
,
c
.
497
T
>
C
,
c
.
424
-
2
A
>
G
)
,
and
4
were
in
exon
7
(
c
.
725
insT
,
c
.
737
G
>
A
,
c
.
757
T
>
C
,
c
.
776
+
1
G
>
A
)
.
The
missense
changes
were
associated
with
severely
decreased
AGT
catalytic
activity
and
negative
immunoreactivity
when
expressed
in
vitro
.
Missense
mutation
c
.
26
C
>
A
,
previously
described
as
a
pathological
mutation
,
had
activity
similar
to
that
of
the
wild-
type
enzyme
.
S
elective
exon
sequencing
can
allow
a
definitive
diagnosis
in
50
%
of
PH
1
patients
.
The
test
offers
a
rapid
turnaround
time
(
15
days
)
with
minimal
risk
to
the
patient
.
Demonstration
of
the
expression
of
missense
changes
is
essential
to
demonstrate
pathogenicity
.
Diseases
Validation
Diseases presenting
"hyperoxaluria"
symptom
cystinuria
neonatal adrenoleukodystrophy
primary hyperoxaluria type 1
This symptom has already been validated