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Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease.
[hydrocephalus with stenosis of the aqueduct of sylvius]
Hirschsprung
disease
(
HSCR
)
stands
as
a
model
for
genetic
dissection
of
complex
diseases
.
In
this
model
,
a
major
gene
,
RET
,
is
involved
in
most
if
not
all
cases
of
isolated
(
i
.
e
.
,
nonsyndromic
)
HSCR
,
in
conjunction
with
other
autosomal
susceptibility
loci
under
a
multiplicative
model
.
HSCR
susceptibility
alleles
can
harbor
either
heterozygous
coding
sequence
mutations
or
,
more
frequently
,
a
polymorphism
within
intron
1
,
leading
to
a
hypomorphic
RET
allele
.
On
the
other
hand
,
about
30
%
of
HSCR
are
syndromic
.
Hitherto
,
the
disease
causing
gene
has
been
identified
for
eight
Mendelian
syndromes
with
HSCR
:
congenital
central
hypoventilation
(
CCHS
)
,
Mowat-
Wilson
(
MWS
)
,
Bardet-
Biedl
(
BBS
)
,
Shah
-
Waardenburg
(
WS
4
)
,
cartilage-
hair
-
hypoplasia
(
CHH
)
,
Smith-
Lemli-
Opitz
(
SLO
)
,
Goldberg-
Sprintzsen
(
GSS
)
,
and
hydrocephalus
due
to
congenital
stenosis
of
the
aqueduct
of
sylvius
(
HSAS
)
.
According
to
the
HSCR
syndrome
,
the
penetrance
of
HSCR
trait
varies
from
5
to
70
%
.
Trisomy
21
(
T
21
)
also
predisposes
to
HSCR
.
We
were
able
to
collect
a
series
of
393
patients
affected
by
CCHS
(
n
=
173
)
,
WS
4
(
n
=
24
)
,
BBS
(
n
=
51
)
,
MWS
(
n
=
71
)
,
T
21
(
n
=
46
)
,
and
mental
retardation
(
MR
)
with
HSCR
(
n
=
28
)
.
For
each
syndrome
,
we
studied
the
RET
locus
in
two
subgroups
of
patients
;
i
.
e
.
,
with
or
without
HSCR
.
We
genotyped
the
RET
locus
in
393
patients
among
whom
195
had
HSCR
,
and
compared
the
distribution
of
alleles
and
genotypes
within
the
two
groups
for
each
syndrome
.
RET
acts
as
a
modifier
gene
for
the
HSCR
phenotype
in
patients
with
CCHS
,
BBS
,
and
Down
syndrome
,
but
not
in
patients
with
MWS
and
WS
4
.
The
frequent
,
low
penetrant
,
predisposing
allele
of
the
RET
gene
can
be
regarded
as
a
risk
factor
for
the
HSCR
phenotype
in
CCHS
,
BBS
,
and
Down
syndrome
,
while
its
role
is
not
significant
in
MWS
and
WS
4
.
These
data
highlight
the
pivotal
role
of
the
RET
gene
in
both
isolated
and
syndromic
HSCR
.
Diseases
Validation
Diseases presenting
"predisposing allele of the ret gene can be regarded as a risk factor for the hscr phenotype in cchs"
symptom
hydrocephalus with stenosis of the aqueduct of sylvius
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