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Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations.
[holt-oram syndrome]
Mutations
in
the
gene
TBX
5
cause
Holt-
Oram
syndrome
(
HOS
)
,
an
autosomal
dominant
disorder
characterized
by
anterior
(
i
.
e
.
,
radial
ray
)
upper
limb
malformations
and
congenital
heart
defects
and
/
or
cardiac
conduction
anomalies
.
The
detection
rate
for
TBX
5
mutations
in
HOS
patients
has
been
given
as
30
-
35
%
in
most
reports
.
However
,
a
detection
rate
of
74
%
was
reported
when
strict
clinical
inclusion
criteria
for
HOS
were
applied
prior
to
TBX
5
analysis
.
Still
,
in
a
significant
proportion
of
typical
HOS
cases
no
mutation
can
be
found
within
the
TBX
5
coding
region
and
flanking
intronic
sequences
.
One
explanation
could
be
that
large
but
submicroscopic
deletions
of
TBX
5
could
cause
HOS
,
yet
only
one
such
TBX
5
deletion
has
been
reported
to
date
.
We
developed
a
quantitative
Real
Time
PCR
strategy
to
detect
large
,
submicroscopic
deletions
in
TBX
5
.
Using
this
assay
,
we
screened
a
total
of
102
TBX
5
mutation
negative
patients
and
discovered
two
novel
intragenic
deletions
.
One
deletion
of
7756
bp
removes
exon
6
and
a
considerable
part
of
the
neighboring
intronic
sequences
,
and
the
other
of
3695
bp
removes
exon
9
with
the
stop
codon
and
the
3
'
UTR
completely
as
well
as
a
part
of
the
preceding
intron
8
.
We
conclude
that
quantitative
Real
Time
PCR
is
a
reliable
method
to
detect
submicroscopic
deletions
within
TBX
5
.
However
,
such
deletions
explain
only
approximately
2
%
of
the
TBX
5
mutational
spectrum
in
HOS
cases
.
In
addition
,
we
also
present
eight
novel
TBX
5
mutations
(
three
nonsense
,
one
splice
mutation
,
four
short
deletions
)
as
detected
by
direct
sequencing
in
21
families
not
previously
analyzed
for
mutations
.
Diseases
Validation
Diseases presenting
"limb malformations"
symptom
holt-oram syndrome
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