Rare Diseases Symptoms Automatic Extraction
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ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia.
[cushing syndrome]
Primary
macronodular
adrenal
hyperplasia
(
PMAH
)
is
a
rare
cause
of
Cushing
's
syndrome
,
usually
characterized
by
functioning
adrenal
macronodules
and
increased
cortisol
production
.
Familial
clustering
of
PMAH
has
been
described
,
suggesting
an
inherited
genetic
cause
for
this
condition
.
The
aim
of
the
present
study
was
to
identify
the
gene
responsible
for
familial
PMAH
.
Forty
-
seven
individuals
of
a
Brazilian
family
with
PMAH
were
evaluated
.
A
single
-nucleotide
polymorphism-based
genome-
wide
linkage
analysis
followed
by
whole-exome
sequencing
were
then
performed
in
selected
family
members
.
Additionally
,
29
other
patients
with
PMAH
and
125
randomly
selected
healthy
individuals
were
studied
to
validate
the
genetic
findings
.
Moreover
,
PMAH
tissue
was
also
analyzed
through
whole-exome
sequencing
,
conventional
sequencing
,
and
microsatellite
analysis
.
A
heterozygous
germline
variant
in
the
ARMC
5
gene
(
p
.
Leu
365
Pro
)
was
identified
by
whole-exome
sequencing
in
a
candidate
genomic
region
(
16
p
11
.
2
)
.
Subsequently
,
the
same
variant
was
confirmed
by
conventional
sequencing
in
all
16
affected
family
members
.
The
variant
was
predicted
to
be
damaging
by
in
silico
methods
and
was
not
found
in
available
online
databases
or
in
the
125
selected
healthy
individuals
.
Seven
additional
ARMC
5
variants
were
subsequently
identified
in
5
of
21
patients
with
apparently
sporadic
PMAH
and
in
2
of
3
families
with
the
disease
.
Further
molecular
analysis
identified
a
somatic
mutational
event
in
4
patients
whose
adrenal
tissue
was
available
.
Inherited
autosomal
dominant
mutations
in
the
ARMC
5
gene
are
a
frequent
cause
of
PMAH
.
Biallelic
inactivation
of
ARMC
5
is
consistent
with
its
role
as
a
potential
tumor
suppressor
gene
.