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Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT.
[canavan disease]
It
has
previously
been
shown
that
specific
microdeletions
and
microduplications
,
many
of
which
also
associated
with
cognitive
impairment
(
CI
)
,
can
present
with
autism
spectrum
disorders
(
ASDs
)
.
Multiplex
ligation-dependent
probe
amplification
(
MLPA
)
represents
an
efficient
method
to
screen
for
such
recurrent
microdeletions
and
microduplications
.
In
the
current
study
,
a
total
of
279
unrelated
subjects
ascertained
for
ASDs
were
screened
for
genomic
disorders
associated
with
CI
using
MLPA
.
Fluorescence
in
situ
hybridization
(
FISH
)
,
quantitative
polymerase
chain
reaction
(
Q-PCR
)
and
/
or
direct
DNA
sequencing
were
used
to
validate
potential
microdeletions
and
microduplications
.
Methylation-sensitive
MLPA
was
used
to
characterize
individuals
with
duplications
in
the
Prader-
Willi
/
Angelman
(
PWA
)
region
.
MLPA
showed
two
subjects
with
typical
ASD
-associated
interstitial
duplications
of
the
15
q
11
-
q
13
PWA
region
of
maternal
origin
.
Two
additional
subjects
showed
smaller
,
de
novo
duplications
of
the
PWA
region
that
had
not
been
previously
characterized
.
Genes
in
these
two
novel
duplications
include
GABRB
3
and
ATP
10
A
in
one
case
,
and
MKRN
3
,
MAGEL
2
and
NDN
in
the
other
.
In
addition
,
two
subjects
showed
duplications
of
the
22
q
11
/
DiGeorge
syndrome
region
.
One
individual
was
found
to
carry
a
12
kb
deletion
in
one
copy
of
the
ASPA
gene
on
17
p
13
,
which
when
mutated
in
both
alleles
leads
to
Canavan
disease
.
Two
subjects
showed
partial
duplication
of
the
TM
4
SF
2
gene
on
Xp
11
.
4
,
previously
implicated
in
X-
linked
non-
specific
mental
retardation
,
but
in
our
subsequent
analyses
such
variants
were
also
found
in
controls
.
A
partial
duplication
in
the
ASMT
gene
,
located
in
the
pseudoautosomal
region
1
(
PAR
1
)
of
the
sex
chromosomes
and
previously
suggested
to
be
involved
in
ASD
susceptibility
,
was
observed
in
6
-
7
%
of
the
cases
but
in
only
2
%
of
controls
(
P
=
0
.
003
)
.
MLPA
proves
to
be
an
efficient
method
to
screen
for
chromosomal
abnormalities
.
We
identified
duplications
in
15
q
11
-
q
13
and
in
22
q
11
,
including
new
de
novo
small
duplications
,
as
likely
contributing
to
ASD
in
the
current
sample
by
increasing
liability
and
/
or
exacerbating
symptoms
.
Our
data
indicate
that
duplications
in
TM
4
SF
2
are
not
associated
with
the
phenotype
given
their
presence
in
controls
.
The
results
in
PAR
1
/
PAR
2
are
the
first
large
-scale
studies
of
gene
dosage
in
these
regions
,
and
the
findings
at
the
ASMT
locus
indicate
that
further
studies
of
the
duplication
of
the
ASMT
gene
are
needed
in
order
to
gain
insight
into
its
potential
involvement
in
ASD
.
Our
studies
also
identify
some
limitations
of
MLPA
,
where
single
base
changes
in
probe
binding
sequences
alter
results
.
In
summary
,
our
studies
indicate
that
MLPA
,
with
a
focus
on
accepted
medical
genetic
conditions
,
may
be
an
inexpensive
method
for
detection
of
microdeletions
and
microduplications
in
ASD
patients
for
purposes
of
genetic
counselling
if
MLPA-identified
deletions
are
validated
by
additional
methods
.
Diseases
Validation
Diseases presenting
"single base changes in probe"
symptom
canavan disease
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