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Haplotype-based approach for noninvasive prenatal diagnosis of congenital adrenal hyperplasia by maternal plasma DNA sequencing.
[congenital adrenal hyperplasia]
Prenatal
diagnosis
of
congenital
adrenal
hyperplasia
(
CAH
)
is
of
clinical
significance
because
in
utero
treatment
is
available
to
prevent
virilization
of
an
affected
female
fetus
.
However
,
traditional
prenatal
diagnosis
of
CAH
relies
on
genetic
testing
of
fetal
genomic
DNA
obtained
using
amniocentesis
or
chorionic
villus
sampling
,
which
is
associated
with
an
increased
risk
of
miscarriage
.
The
aim
of
this
study
was
to
demonstrate
the
feasibility
of
a
new
haplotype-based
approach
for
the
noninvasive
prenatal
testing
of
CAH
due
to
21
-
hydroxylase
deficiency
.
Parental
haplotypes
were
constructed
using
target-region
sequencing
data
of
the
parents
and
the
proband
.
With
the
assistance
of
the
parental
haplotypes
,
we
recovered
fetal
haplotypes
using
a
hidden
Markov
model
(
HMM
)
through
maternal
plasma
DNA
sequencing
.
In
the
genomic
region
around
the
CYP
21
A
2
gene
,
the
fetus
inherited
the
paternal
haplotype
'
0
'
alleles
linked
to
the
mutant
CYP
21
A
2
gene
,
but
the
maternal
haplotype
'
1
'
alleles
linked
to
the
wild-
type
gene
.
The
fetus
was
predicted
to
be
an
unaffected
carrier
of
CAH
,
which
was
confirmed
by
genetic
analysis
of
fetal
genomic
DNA
from
amniotic
fluid
cells
.
This
method
was
further
validated
by
comparing
the
inferred
SNP
genotypes
with
the
direct
sequencing
data
of
fetal
genomic
DNA
.
The
result
showed
an
accuracy
of
96
.
41
%
for
the
inferred
maternal
alleles
and
an
accuracy
of
97
.
81
%
for
the
inferred
paternal
alleles
.
The
haplotype-based
approach
is
feasible
for
noninvasive
prenatal
testing
of
CAH
.
