1. ISPD 2013 MEETING PRESENTATION
Controversies in prenatal diagnosis 3: should everyone
undergoing invasive testing have a microarray?
John A. Crolla1
, Ronald Wapner2
and Jan M. M. Van Lith3*
1
Wessex Regional Genetics Laboratory, Salisbury, UK
2
Columbia University College of Physicians and Surgeons, New York, NY, USA
3
Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands
*Correspondence to: Jan M. M. Van Lith. E-mail: j.m.m.van_lith@lumc.nl
Funding sources: None
Conflicts of interest: None declared
The possibility to obtain fetal cells during pregnancy has
opened the way to prenatal diagnosis of genetic disorders. This
started in 1996/1967, when Steele and Breg,1
and Jacobson and
Barter,2
reported the possibility to karyotype fetal cells and
second trimester amniocentesis for chromosomal disorders.
In 1983, Simoni et al.3
described karyotyping of uncultured
chorionic villi, moving prenatal diagnosis forward to the first
trimester. Until recently, these invasive procedures and
karyotyping remained the gold standard in prenatal diagnosis
for genetic disorders.
Down syndrome is related to maternal age, and this was the
main indication for invasive procedures until the introduction
of risk assessment in early pregnancy in 1988.4
This risk
assessment refined to the combination screening test and/or
the quadruple test.
Another important development in diagnosing fetal anomalies
was the introduction of ultrasound. This developed from the
1980s onwards. Structural anomalies detected by ultrasound
are in most cases followed by invasive prenatal diagnosis. This
is the other main indication to offer invasive testing.
In the late 1990s, new genetic techniques, such as
fluorescence in situ hybridization (FISH), multiplex ligation-
dependent probe amplification, and PCR were implemented,
referred to as rapid aneuploidy testing. These techniques led
to earlier results when compared with karyotyping, were often
cheaper; however, only selected chromosome regions were
tested. Some thought this to be advantageous, others thought
it to be too limited.5
This change started discussions on what to test for. The
screening tests mainly focused on Down syndrome, whereas
the invasive tests covered a much broader range of chromosomal
disorders. In case of ultrasound anomalies, a broader test range
is needed. The genetic techniques further developed, and
microarrays are routinely used in postnatal genetic diagnosis
covering a broader range of genetic disorders. There are good
reasons to introduce microarrays in prenatal diagnosis; however,
it does have disadvantages.6
The question for the debaters (John Crolla and Ronald
Wapner) at the 17th International Conference was: ‘Should
everyone undergoing invasive testing have a microarray?’.
IN FAVOR (RONALD WAPNER)
For over 50 years, karyotyping has been the only technology used
for prenatal cytogenetic diagnosis, but – more recently – newer
and more robust techniques have entered the field. One of these
is chromosomal microarray analysis (CMA). CMA has a
number of significant advantages over karyotyping, which
suggest that it should be made available to all patients
undergoing invasive prenatal testing (and perhaps should be
offered to all pregnant women).
The most important technical advantage of CMA is the
ability to detect all of the unbalanced cytogenetic findings
presently identified by karyotyping, whereas – in addition –
having markedly superior resolution allowing identification
of much smaller genomic alterations. At best, a karyotype
has a resolution between 7 and 10 million base pairs
(bp), whereas chromosomal microarray has the ability to
identify microdeletions and duplications in the 100 to
300 kb range.
Identification of cytogenetic alterations too small to be seen
by karyotype has major clinical importance. Most of the well
described microdeletion and microduplication syndromes are
secondary to copy number variants in the 1.5 to 3.5 Mb range.
In addition, there are now well described non-syndromal
effects of microdeletions and duplications resulting from copy
number variants smaller than 1 Mb.7
This improved resolution
has led to CMA becoming the first tier test for postnatal
evaluation of children with congenital anomalies, dysmorphic
features, and neurocognitive difficulties. In these children,
microarray analysis has an incremental 10% to 15% yield of
clinically relevant findings over karyotype. This advantage
alone should be sufficient to recommend microarray analysis
on all prenatal samples.7
Prenatal Diagnosis 2014, 34, 18–22 © 2013 John Wiley & Sons, Ltd.
DOI: 10.1002/pd.4287

2. Chromosomal microarray analysis has additional technical
advantages beyond improved resolution. It provides direct
mapping of aberrations to their location in the genome
sequence, which significantly improves the ability to define
marker chromosomes, to confirm that de novo balanced
translocations are actually balanced, and to identify the specific
start and stop points of these changes. In contrast, in karyotyping
the location of the abnormality is not nearly as precise.
Another technological advantage of CMA is that it is amenable
to automation and quite easily undergoes quality control,
whereas the resolution and reliability of karyotyping is dependent
on the experience and abilities of the cytogenetics laboratory.
CMA is also capable of being performed on uncultured cells and
does not require good metaphase spreads, which should result
in higher throughput with more rapid reporting time.8
In the long
run, because CMA requires less manpower, it should become
more cost-effective than karyotyping.
The incremental information provided by CMA improves
our ability to counsel patients identified with a pregnancy
having a fetal structural anomaly. Multiple studies9,10
have
demonstrated that in these cases a clinically relevant copy
number variant will be identified, which can alter prognostic
counseling. Routine use of CMA reveals that this occurs in
approximately 6% of pregnancies with a normal karyotype.8,11
For example, counseling a patient whose fetus has a cardiac
defect secondary to a 22q11.2 deletion requires (in addition
to details about surgical correction of the defect) discussion
of the associated learning and developmental disabilities.12
Understanding the etiology therefore is an important adjunct
to the parental counseling session.
Although 22q11.2 deletions are routinely tested for when a
cardiac structural abnormality is identified, it is not the only
microdeletion or duplication, in which cardiac malformations
are associated with intellectual disability (Table 1). In our
experience with the National Institute of Child Health and
Human Development (NICHD) prenatal microarray study,13
in which 297 fetuses with structural cardiac defects were
evaluated, only one third of the causative copy number
variants were deletions of 22q11.2. In other words, if only FISH
for the 22q11.2 deletion were performed, two thirds of the
families having a copy number variant that could alter the
prognosis would not be aware of this.
Presently, most practitioners recommend invasive prenatal
diagnosis when the ultrasound findings are suggestive of a
common autosomal aneuploidy. We are now aware that
microdeletions and duplicatons may have more subtle in utero
phenotypes so that identification of these requires expanding
the ultrasound criteria used for invasive diagnosis. Table 2
demonstrates a number of single fetal structural abnormalities
identified in the NICHD prenatal array study13
that are not
routinely associated with aneuploidy but have a high
frequency of having a microdeletion or duplication.
Although it is clear that CMA has incremental value in
evaluating structurally abnormal pregnancies, it is also
important to explore its use in patients undergoing invasive
testing for more routine indications, such as advanced
maternal age (AMA) or positive aneuploid screening. Of the
slightly less than 3000 patients without anomalies evaluated
in the NICHD prenatal microarray study, just short of 2000
were sampled for AMA and 729 for positive screening. In each
of these categories, approximately 1 in 60 pregnancies were
identified as having a clinically relevant microdeletion or
duplication.8
Although some of these microdeletions and
duplications had mild phenotypes, approximately 1 in 125
without a structural abnormality is known to be associated
with significant neurocognitive impairment.8
This information
can be valuable for many parents in making reproductive
decisions, and it will have significant value in the future
management of the child.
When testing a structurally normal pregnancy, the
identification of a copy number variant early in gestation
may suggest the potential of finding a subsequent fetal
structural anomaly later in gestation. In essence, the genotype
identified with CMA will give the practicing physician the
knowledge to do a targeted fetal surveillance study later in
gestation to better delineate the phenotype.
One of the concerns about prenatal CMA is that there may
be results that do not have severe and/or lethal consequences.
Table 2 Genetic abnormalities seen in patients with a Single
Fetal Structural Defect (N = 845)
System N
Abnormal
karyotype (%) Abnormal CMA (%)
Cardiac 92 16 13
IUGR 49 10 9
NT ≥ 3.5 mm 337 50 4
CNS 95 13 4
Skeletal 23 4 4
Others 234 12 5
CMA, chromosomal microarrays; IUGR, intrauterine growth restriction.
Table 1 Significant microdeletions associated with congenital
heart disease
Copy number
Variant Syndrome Additional phenotype
Del 1p36 ID
Del 1q21.1 Mild ID
Del p16.3 Wolf–Hirschhorn
syndrome
Microcephaly, severe ID, and
seizure
Del 5p15.2 Cri-du-chat Severe ID
Del 5q35.2 ASD and conduction
defect
Del 7q11.23 Williams–Bueren
syndrome
Cognitive deficits and infantile
hypocalcemia
Del 8p23.1 ID
Del 9 q34
Del 11 q23-qter Jacobsen syndrome ID
Del 16p13.3 Rubinstein Taybi + CHD ID
Del 20p12.2 Alagille syndrome Liver disease
Del 22q11.2 DiGeorge syndrome ID, schizophrenia
ID, intellectual disability.
Controversies in prenatal diagnosis 3 19
Prenatal Diagnosis 2014, 34, 18–22 © 2013 John Wiley & Sons, Ltd.

3. This raises the question of whether these disorders should be
diagnosed in utero. However, we must realize that as new
prenatal tests deliver improved resolution, they offer
increasing options for use of the genetic information.
Discovery of many of these findings can assist the parents in
seeking appropriate care early in the infant’s life. For example,
fetuses identified to have a microdeletion or duplication
associated with a high risk for autism could initiate treatment
much earlier, which has been demonstrated to have a marked
improvement in the long-term prognosis for the child.
Similarly, children at risk for learning disorders could have
early intervention before starting standard schooling.
One other concern mentioned about CMA is the
identification of variants of uncertain clinical significance. This
is a relatively minor concern that will shrink over time. Our
NICHD study8
demonstrated that between 2007 and 2012, the
classification of copy number variants discovered in utero
and classified as uncertain decreased from 2.5% to 1.5%.
Interestingly, the majority of findings initially identified as
uncertain have subsequently been confirmed as pathogenic.8
As additional information from the use of CMA and more cases
of similar microdeletions and duplications are documented,
the number of findings of uncertain clinical significance will
continue to fall. One must remember also that findings of
unknown clinical significance occur routinely with
karyotyping. Han et al.14
in 2008 demonstrated with
karyotyping that findings of uncertain clinical significance
occurred in almost 1% of cases. Chang et al.15
in 2012
demonstrated a similar 1% incidence of findings of uncertain
significance in a similar cohort. Many of the uncertain findings
in karyotyping, such as de novo, apparently balanced
translocations or marker chromosomes are actually better
defined using CMA. Therefore, the primary use of CMA will
minimize these numbers as well.
In conclusion, it is relatively clear that the increased
detection afforded by CMA makes it the ideal test to become
the first tier tool for prenatal diagnosis. Not only should one
recommend it as the first tier test for anyone having invasive
testing, the over 1% frequency of clinically relevant findings
in all pregnancies suggests that all patients should be made
aware of the technology and have the option of having their
pregnancy evaluated by CMA.
AGAINST (JOHN A. CROLLA)
For the past 40years, conventional cytogenetics has been the
main laboratory technique for the prenatal diagnosis of
chromosomal abnormalities. Ironically, in the context of this
discussion, the principal purpose of cytogenetic prenatal
diagnosis has been intrinsically linked to risk factors associated
with Down syndrome, initially increased maternal age. Over the
past two decades, the maternal age risk has been combined with
maternal serum and ultrasound markers to provide more robust
risk algorithms associated with a risk of a Down syndrome
pregnancy.16
The irony alluded to above is that, from the outset,
conventional cytogenetics was capable of detecting and reporting
structural (e.g. balanced and unbalanced translocations) as well
as the common autosomal and sex chromosome numerical
abnormalities (including trisomy 21) and so has a long history of
dealing with chromosome abnormalities incidental to the
primary referral reason.
Conventional cytogenetics remained the primary prenatal
diagnostic test until recently when molecular techniques were
developed to provide fast and accurate methods for the
identification of the common autosomal and sex chromosome
aneuploidies. In many countries, quantitative fluorescence
polymerase chain reaction (QF-PCR) is now the primary invasive
prenatal diagnostic test for trisomies 13, 18, 21, and for numerical
sex chromosome abnormalities17
but because of concerns about
missing structural chromosome abnormalities,18
QF-PCR is
usually supplemented with a karyotype result.
Although technical advances in prenatal cytogenetic
diagnostics have remained relatively static, by comparison the
past decade has seen a revolution in postnatal cytogenetics
driven by the introduction of array comparative genome
hybridization (aCGH) driven initially by proof of principal
studies which showed that if aCGH was targeted to defined
clinical populations diagnostic yields (of pathogenic sub-
microscopic deletions and duplications) were~ 20% higher than
achieved using karyotyping.19,20
Contemporaneously, aCGH
studies also showed that genomic imbalances, called Copy
Number Variants (CNV) were also present in clinically normal
control populations.21,22
By 2010, aCGH had largely replaced
karyotyping for patients with neurodevelopmental and/or
congenital abnormalities in most major cytogenetic centers in
the USA, UK, Europe, and Australasia, and its implementation
was fostered in part by large-scale collaborations such as the
International Standard for Cytogenomic Array Consortium,
which in turn resulted in a key consensus statement .7
Compared with postnatal cytogenetics, the uptake and use of
aCGH in the prenatal area has been slower with a more cautious
approach to it’s implementation.23
Early proof of principles
studies utilized previously characterized chromosomally
abnormal prenatal samples and a targeted array to determine
the sensitivity of detection rates between conventional
cytogenetics and aCGH.24
However, over the past 2 years, large
prenatal aCGH scale studies have been published, which a priori
appear to show that aCGH can improve the detection of
‘clinically relevant CNVs’ in the presence of a normal karyotype
by ~ 3%.8,9,25,26
This diagnostic pick up rate is significantly higher
if aCGH is targeted to fetuses with ultrasound abnormalities and
this ranges from 6% to 13% depending on the study design.27–29
Amongst women undergoing prenatal, aCGH for maternal age
or other indications other than fetal anomalies, the detection
rate of clinically significant CNVs was reported to be ~ 1%.8
The articles quoted earlier have recently been collated by
Callaway et al.30
and on the face of it, the increased detection
rate achieved by prenatal aCGH appears compelling. However,
it is important to take into account that at least some of the
studies quoted have been carried out within a defined research
protocol8
and so aspects of the clinical use of prenatal aCGH
requires further consideration before the technology can be
used to routinely replace karyotyping either partly or
completely. The principal reasons for caution at this stage are
summarized below.
At the heart of a debate about prenatal microarrays lies the
interpretation of a CNV (or CNVs) against which the clinician
J. A. Crolla et al.20
Prenatal Diagnosis 2014, 34, 18–22 © 2013 John Wiley & Sons, Ltd.

4. (fetal medicine consultants, obstetricians, and geneticists) and
the laboratory scientist will have relatively limited clinical and
phenotypic information to make a judgment call on the
possible clinical consequences of a significant number of
aCGH detected imbalances. Clearly, at one end of the
spectrum, there are clearly defined micro deletion and micro
duplication syndromes, which show high penetrance, are
associated with well characterized clinical phenotypes and, if
found prenatally, can be associated with relatively robust and
accurate genetic counseling. However, such clear cut
correlations in the data quoted earlier represent the minority
of cases reported, and at the other end of the same spectrum
are rare or unique CNVs with no know associated clinical
phenotypes [classified as Variants of Uncertain Clinical
Significance (VOUS)]. Between these two ends of the spectrum
lie a number of CNVs with highly variable clinical expressivity
associated with incomplete penetrance, which are problematic
enough in the postnatal area but in the context of a prenatal
diagnosis cause significant diagnostic, counseling, and ethical
dilemmas.31
Into this already complex mix, there will also be
the admittedly rare but nevertheless difficult cases where the
CNV(s) detected may be incidental to the referral reason (e.g.
dominant cancer gene loci and other late onset disorders)
but for which a well defined protocol must be in place before
widespread prenatal aCGH can be implemented.
The proponents for an immediate implementation of
prenatal aCGH suggest that the speed with which data derived
from the clinical use of postnatal aCGH is accumulating means
that the proportion of cases currently defined as VOUS will
decline as more genotype/phenotype data emerge, but this
does not take into consideration how prenatally detected CNVs
with variable penetrance or VOUS should be handled now. The
study by Wapner et al.8
in 2012 and an ongoing research study
in the UK called EACH (Evaluation of Array Comparative
Genomic Hybridization in prenatal diagnosis of fetal
abnormalities) both have made use of an expert review panel
to determine whether or not specific VOUS should be reported
to the patient or not. In this context, to date approximately
3.5% of aCGH results had been referred to the EACH review
committee, which consists of five consultant clinical geneticists
and five consultant clinical cytogeneticists. Approximately half
of the cases referred for EACH review were recommended for
reporting and half for not reporting. Although tertiary review of
this type already exists within some postnatal aCGH centers, it
is vital that before prenatal aCGH is widely adopted the
resourcing, logictics, and resource implications of such tertiary
review groups must be fully considered.
Another important aspect of prenatal aCGH implementation
involves the design of the array and whether the analyses
should be targeted to known pathogenic regions together with
a low density backbone coverage, or the backbone coverage
should be higher density together with higher probe coverage
of known pathogenic CNVs.32
The final decision of which
platform to adopt may also be complicated not only by
scientific evidence but also by the health economics driving
the method of delivery adopted by different countries.33
There
is also the unresolved discussion on whether prenatal aCGH
should be limited to dosage analysis using oligos or single
nucleotide polymorphisms (SNPs) or should also routinely
incorporate the use of SNPs to detect possibly pathogenic
segmental or whole chromosome uniparental disomy.34
The lag between proof of principle studies showing, in a
research context, the clinical utility of a novel technique and
the widespread application of the novel technique in clinical
and laboratory practice can be significant, and for the
postnatal application of aCGH, this took several years in many
countries including the UK. Technological advances are so
rapid that important laboratory external quality assurances
schemes for novel technologies often lag behind their
implementation, and for prenatal aCGH no such schemes have
yet been developed or incorporated into laboratory practice.
Furthermore, to date there are no clear guidelines published
for the use of prenatal aCGH from either the USA or European
stakeholders although the International Society for Prenatal
Diagnosis (ISPD) is currently drafting such guidelines.
Finally, in the ISPD debate in Lisbon, the question put was
‘should everyone undergoing invasive testing have a
microarray’. The answer to this question is ‘not yet’ for two
principal reasons. First, there are simpler, cheaper, and more
cost-effective ways of testing for Down syndrome and the other
common aneuploidies following invasive prenatal diagnosis
(e.g. QF-PCR). Furthermore, the availability and gradual
adoption of non-invasive next generation sequencing
approaches to the diagnosis of Down syndrome is changing the
prenatal screening and subsequent testing protocols for prenatal
health care providers worldwide. Prenatal aCGH should
therefore only be used once the common aneuploidies have
been excluded by other methods. Second, although it is clear
that postnatal aCGH has contributed greatly to our
understanding of the underlying pathology of many CNVs, the
fact remains that many of the reported prenatal CNVs are either
unique or VOUS and therefore require detailed interpretation
utilizing multidisciplinary teams of laboratory scientists, genetic
counselors, and fetal medicine practitioners. The cost and
resource implications of this needs to be considered so that,
once implemented, prenatal aCGH can make a positive
contribution to improving diagnosis and prognosis.
CONCLUSION
Around 50 years ago, prenatal diagnosis became possible for
chromosomal disorders. Ultrasound further opened up the
possibility to diagnose fetal abnormalities early in pregnancy.
Nowadays, a great part of fetal structural and genetic
anomalies can be diagnosed early in pregnancy, thereby
providing reproductive choices to future parents and early
treatment options for newborns improving outcome and
prognosis.
New genetic techniques have evolved rapidly in recent years.
CMA has replaced karyotyping in postnatal diagnosis. Its
implementation in prenatal diagnosis has been slower and
more cautious. The debate clearly shows that CMA increases
the diagnostic scope and brings with it new challenges.
Both debaters agree that CMA will have a place in prenatal
diagnosis. Its exact application needs further evaluation, and
the implementation of quality system is a prerequisite.
Controversies in prenatal diagnosis 3 21
Prenatal Diagnosis 2014, 34, 18–22 © 2013 John Wiley & Sons, Ltd.

5. WHAT’S ALREADY KNOWN ABOUT THIS TOPIC?
• Chromosomal microarrays (CMA) are routinely used in postnatal
genetic diagnosis.
• CMA is technically applicable in prenatal diagnosis.
• Pros and cons of routine use are discussed as follows: technical
aspects and design of array, yield, interpretation of CNV and
variances of unknown significance (VOUS), quality control regimens.
WHAT DOES THIS STUDY ADD?
• Pros and cons of routine use are discussed as follows:
technical aspects, and design of array, yield, interpretation
of CNV and variances of unknown significance (VOUS), quality
control regimens.
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