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FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.
[kallmann syndrome]
Harstfield
syndrome
is
the
rare
and
unique
association
of
holoprosencephaly
(
HPE
)
and
ectrodactyly
,
with
or
without
cleft
lip
and
palate
,
and
variable
additional
features
.
All
the
reported
cases
occurred
sporadically
.
Although
several
causal
genes
of
HPE
and
ectrodactyly
have
been
identified
,
the
genetic
cause
of
Hartsfield
syndrome
remains
unknown
.
We
hypothesised
that
a
single
key
developmental
gene
may
underlie
the
co
-occurrence
of
HPE
and
ectrodactyly
.
We
used
whole
exome
sequencing
in
four
isolated
cases
including
one
case-parents
trio
,
and
direct
Sanger
sequencing
of
three
additional
cases
,
to
investigate
the
causative
variants
in
Hartsfield
syndrome
.
We
identified
a
novel
FGFR
1
mutation
in
six
out
of
seven
patients
.
Affected
residues
are
highly
conserved
and
are
located
in
the
extracellular
binding
domain
of
the
receptor
(
two
homozygous
mutations
)
or
the
intracellular
tyrosine
kinase
domain
(
four
heterozygous
de
novo
variants
)
.
Strikingly
,
among
the
six
novel
mutations
,
three
are
located
in
close
proximity
to
the
ATP
's
phosphates
or
the
coordinating
magnesium
,
with
one
position
required
for
kinase
activity
,
and
three
are
adjacent
to
known
mutations
involved
in
Kallmann
syndrome
plus
other
developmental
anomalies
.
Dominant
or
recessive
FGFR
1
mutations
are
responsible
for
Hartsfield
syndrome
,
consistent
with
the
known
roles
of
FGFR
1
in
vertebrate
ontogeny
and
conditional
Fgfr
1
-
deficient
mice
.
Our
study
shows
that
,
in
humans
,
lack
of
accurate
FGFR
1
activation
can
disrupt
both
brain
and
hand
/
foot
midline
development
,
and
that
FGFR
1
loss
-of-function
mutations
are
responsible
for
a
wider
spectrum
of
clinical
anomalies
than
previously
thought
,
ranging
in
severity
from
seemingly
isolated
hypogonadotropic
hypogonadism
,
through
Kallmann
syndrome
with
or
without
additional
features
,
to
Hartsfield
syndrome
at
its
most
severe
end
.
Diseases
Validation
Diseases presenting
"severe end"
symptom
dentin dysplasia
hydrocephalus with stenosis of the aqueduct of sylvius
kallmann syndrome
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