Editorial. Whole-genome array as a first-line cytogenetic test in prenatal diagnosis
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1 Ultrasound Obstet Gynecol 2015; 45: Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Editorial Whole-genome array as a first-line cytogenetic test in prenatal diagnosis M. I. SREBNIAK*, D. VAN OPSTAL, M. JOOSTEN, K. E. M. DIDERICH, F. A. T. DE VRIES, S. RIEDIJK, M. F. C. M. KNAPEN, A. T. J. I. GO, L. C. P. GOVAERTS and R.-J. H. GALJAARD Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands; Stichting Prenatale Screening Zuidwest Nederland, Rotterdam, The Netherlands *Correspondence. ( m.srebniak@erasmusmc.nl) Introduction The main goal of cytogenetic prenatal diagnosis is to inform prospective parents about the chromosomal status of their fetus. A chromosomal aberration usually causes an abnormal phenotype in childhood. Prenatal whole-genome cytogenetic diagnosis was for a long time dependent on karyotyping, which requires time-consuming cell culturing, has a limited resolution (5 10 Mb) and is dependent on optimal harvesting and chromosome staining conditions. Nowadays, genomic microarray technology allows whole-genome testing at a higher resolution and it can be applied to uncultured fetal material, allowing shorter reporting times when compared with classical cytogenetic techniques. Genomic microarray testing has been recommended for routine postnatal cytogenetics in cases of intellectual disability and/or multiple congenital anomalies 1, and for prenatal diagnosis in cases of fetal ultrasound anomalies 2. However, its implementation for all indications in prenatal genetic diagnosis is still under discussion 3 6. The main arguments against offering prenatal array testing for all indications are the possibility of detecting: (1) CNVs causing well-described clinically significant anomalies not related to the initial indication (unexpected diagnoses); (2) CNVs associated with a variable expressivity and heterogeneity of clinical features, with an as yet unquantifiable chance of an abnormal phenotype if found prenatally (so called susceptibility loci (SL) for neurodevelopmental disorders); and (3) variants of unknown clinical significance (VOUS). Such findings may complicate genetic counseling 7 12 and these issues raise further questions, such as which outcomes of genomic microarrays should be reported to pregnant couples? Should they be offered a choice regarding about which possible array outcomes they wish to be informed? Is extensive genetic pretest counseling in every case necessary and feasible in clinical practice? Since this new technology is already present in prenatal clinics, rather than debating whether array testing should be performed for all referrals of invasive cytogenetic prenatal diagnosis, we should instead be discussing how to meet this challenge. In this Editorial, we review the current international status regarding the use of array technology for prenatal diagnosis. We discuss platforms and testing resolution, indications, counseling, (possible problematic) findings and the decision regarding what should be reported to the future parents. Microarray as a laboratory test Genomic array platform and testing resolution There are three main types of genomic microarray available: bacterial artificial chromosome (BAC) arrays, oligonucleotide arrays and single nucleotide polymorphism (SNP)-based arrays 13,14. In the case of BAC and oligonucleotide arrays, fragmented DNA from both the patient and a control sample (labeled in different colors with fluorescent dye) are hybridized to matching probes on a chip and the intensity of both colors is compared. Abnormal ratios between control and patient DNA reveal losses or gains; therefore, this technique is called array-based comparative genomic hybridization (array-cgh). SNP arrays use single nucleotide polymorphisms, genome positions at which there are one of two distinct nucleotide residues (the so-called A and B alleles), each of which appears in a significant portion of the human population. By labelling the A and B alleles with different colors and comparing the intensities of these colors ( B-allelic plot ), the loss or gain of alleles is revealed. Both array-cgh and SNP arrays can detect unbalanced (sub)microscopic chromosomal abnormalities, but SNP arrays also provide genotype information (based on the A and B alleles) at multiple SNP loci throughout the genome, which makes it the preferred microarray method (Table 1). The main reason that we favor SNP arrays (although non-snp arrays, i.e. array-cgh, are as effective in detecting submicroscopic CNVs) is that this can be used as a rapid stand-alone test, while a non-snp array has to be supplemented with rapid aneuploidy detection (RAD) and testing for maternal cell contamination in all cases. A SNP array detects all relevant unbalanced aberrations, detects additional aberrations not detectable by non-snp arrays 15,16 and recognizes samples contaminated with maternal tissue or with low mosaicism within the same experiment. Moreover, the B-allelic frequency plot supports the CNV findings and the need to validate the findings is minimized. Examples of recent studies and the diagnostic yield of SNP arrays are summarized in Table 2. Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd. EDITORIAL
2 364 Srebniak et al. Table 1 Advantages of single nucleotide polymorphism (SNP)-based array over non-snp array in the prenatal setting 1 SNP array can detect triploidy 21, and therefore RAD is not mandatory prior to testing. 2 SNP array is able to detect lower-level mosaicism (as low as 5% depending on origin) Large ROH can suggest uniparental disomy 116,117, which may be clinically relevant when involving chromosomes 6, 7, 11, 14, 15 and Excessive ROH throughout the genome may reveal consanguinity 15, potentially leading to diagnosis of a recessive genetic disorder SNP array is very sensitive to detect MCC. Therefore, an MCC test is not mandatory before SNP array SNP array helps to recognize twin twin contamination and chimerism SNP array helps to recognize molar pregnancies ((mosaic) homozygosity of all chromosomes). 8 SNP array usually requires less DNA and therefore is better for uncultured material B-allelic frequency plot of SNP array supports copy number variation findings (loss is always accompanied by ROH and gain by multiple B-allelic lines); therefore, the need to validate these findings is minimized. 10 Because of ability to detect MCC and triploidy, SNP array may be used as stand-alone test, while non-snp array has to be supplemented with MCC testing and RAD in all cases. MCC, maternal cell contamination; RAD, rapid aneuploidy detection; ROH, regions of homozygosity. Every type of microarray uses chips containing DNA probes. The genomic location of the probes and the number of probes on the chip determines the targeted or whole-genome character of the array platform and its resolution. The higher the probe density, the higher the resolution, i.e. the smaller the aberrations that can be detected. The first question that arises, therefore, is the choice of array platform. This involves choosing either whole-genome array or targeted array and, in the case of targeted array, choosing whether it is with or without a low-resolution whole-genome backbone. Some researchers follow a targeted-array approach, using platforms that cover known clinically relevant regions/syndromes with a low-resolution backbone The advantage of such a choice is that there is a smaller chance of unexpected diagnoses and detection of VOUS or SL for neurodevelopmental disorders. Others advocate that whole-genome diagnosis is to be preferred over a targeted approach in order to maximize the diagnostic yield 20,21 and ensure detection of recently discovered syndromes that may not be covered by a targeted design 22,23. Most of the recently published prenatal cohorts seemed to employ a genome-wide non-targeted array or an array with genome-wide coverage and enrichment of target regions 33,34. A consensus about minimum testing resolution should be established in guidelines, as has been done previously for karyotyping 35. However, due to the diversity of array platforms, it is challenging to establish the minimum array resolution that should be used in the prenatal setting 29, and there has been considerable variation in the resolutions used by different researchers. Authors using high-density whole-genome oligonucleotide or SNP arrays use a resolution of Mb, which is the resolution limit of most of the older platforms, and therefore they have reported (and analyzed) only variants larger than 0.1Mb 36 or Mb 32. For targeted platforms, the situation is different. For example, Hillman and colleagues 18 report findings larger than 2 Mb in the backbone and 0.2 Mb in the targeted regions. Others state that CNVs smaller than a certain threshold (e.g. 0.4 Mb) are investigated only if relevant for the referral indication 26. However, to know which CNV is clinically relevant, the gene content of any variant should be analyzed. Another approach is to filter results of a very high-density array platform. By doing so, Filges and colleagues 37 did not evaluate findings smaller than 0.4 Mb although their platform would allow this. Hillman et al. 34 investigated the diagnostic yield and frequency of VOUS in a cohort of 62 fetuses with ultrasound anomalies tested with a 1-Mb BAC array in the clinical setting and with a 60-K platform in the research setting. They noticed an increased diagnostic yield (additional 4.8%), but also an increased frequency of VOUS (8%) in the research compared with the clinical setting, and questioned the usefulness of high-resolution testing in the absence of consensus regarding the reporting of VOUS. Srebniak et al. 38, seeking to replace karyotyping with a lower-resolution array in prenatal cases without ultrasound anomalies, attempted to determine the optimal analysis resolution in a cohort of 465 fetuses evaluated retrospectively with several levels of resolution. They found a resolution of 0.5 Mb to be optimal, with an acceptable frequency of VOUS in uneventful pregnancies. Vermeesch and colleagues 39 previously recommended a minimum resolution of 0.2 Mb, but both the Belgian national consensus guideline 40 and recent American College of Medical Genetics (ACMG) Standards and Guidelines 41 suggest a minimum (backbone) resolution of 0.4 Mb. It would be beneficial to use the same array platform (if necessary with different analysis resolutions) for both post- and prenatal samples. This would simplify comparison of family members who were diagnosed in different settings and re-analysis with higher resolution if anomalies appear later in pregnancy or at birth 37,38. Because of the variety of indications in the prenatal setting, the discussion on minimum resolution should perhaps be conducted in the context of a specific referral indication rather than in general 38,42, just as was done in the case of karyotyping 35. Testing of parental DNA Parental testing for fetal CNVs is necessary for genetic counseling regarding recurrence risk. Moreover, inheritance is an important factor in CNV interpretation, especially in cases of (potentially pathogenic) VOUS. It has been proposed that an inherited CNV from a
3 Editorial 365 Table 2 Recent examples of prenatal cohorts studied with single nucleotide polymorphism (SNP)-based array and diagnostic yield Reference Cohort selection/inclusion criteria Number of fetuses Diagnostic yield (%)* Tyreman et al. (2009) 121 Major ultrasound anomaly or multiple soft markers, normal karyotype and 22q11 FISH Faas et al. (2010) 122 Normal karyotype, ultrasound anomaly Faas et al. (2012) 32 Ultrasound anomaly, normal RAD Srebniak et al. (2012) 49 Ultrasound anomaly (karyotype unknown in some) Reddy et al. (2012) 64 Stillbirth Ganesamoorthy et al. (2013) 29 Ultrasound anomaly Schmid et al. (2013) 27 Structural fetal defect, normal karyotype Liao et al. (2014) 84 Structural fetal malformation on ultrasound, normal karyotype Charan et al. (2014) 24 Fetal anomaly Liao et al. (2014) 30 Heart defect with or without additional anomaly Oneda et al. (2014) 31 Normal karyotype, any indication Wang et al. (2014) 123 Miscarriage Zilina et al. (2014) 124 Diverse indications Van Opstal et al. (2014) 73 Fetus without ultrasound anomaly Srebniak et al. (in prep.) Ultrasound anomaly Percentage of pathogenic findings is highly dependent on cohort selection and testing resolution. *Diagnostic yield: percentage of submicroscopic clinically relevant or pathogenic findings. FISH, fluorescence in-situ hybridization; RAD, rapid aneuploidy detection. phenotypically normal parent may be interpreted as (likely) benign 8 10,21,43. However, several studies have shown that the situation is not so straightforward. CNVs associated with a risk for neurodevelopmental disorders, so called SLs, have been discovered Many are inherited from a normal or apparently normal parent; thus, when interpreting inherited CNVs, the possibility of association with an abnormal phenotype of variable expressivity, incomplete penetrance and/or heterogeneity of clinical features should be taken into account and it must be borne in mind that parental testing does not always clarify the clinical significance of a CNV 42. Despite these limitations, parental testing can be helpful for the interpretation of the array result, especially in cases of (potentially pathogenic) VOUS, and it facilitates post-test counseling 47. Moreover, parental array data are an important source of information regarding rare CNVs in a general population and comprise an important set of in-house control data, indispensable for rapid interpretation of array results. There are two possible approaches in parental testing. Parental testing could be performed after detection of a (possibly) pathogenic variant in the fetus 26,29,48. This method is most effective when relatively few VOUS are expected because of the use of a targeted or lower-resolution platform 38 or in first-trimester pregnancy testing. Following such an approach, the invasive procedure should be planned sufficiently early as to allow subsequent parental testing and proper patient care, including: pretest counseling, sampling, fetal DNA array testing, post-test genetic counseling, parental DNA array testing, post-test genetic counseling, time for reconsideration and, if needed, psychological support for the parents, especially if there are time constraints for pregnancy termination. An alternative approach involves testing parental and fetal samples simultaneously. To ensure short reporting times, speed up the analysis and avoid parental anxiety, this approach is recommended when many events per individual have to be evaluated after high-resolution whole-genome testing 49 and in advanced pregnancies 32. Is there still a role for rapid aneuploidy detection (RAD) and karyotyping? RAD for the most common aneuploidies (trisomies 13, 18 and 21 and sex chromosomal aneuploidies) and triploidy was developed mainly to shorten the reporting time of preliminary targeted prenatal cytogenetic results in amniotic fluid. Karyotyping of amniotic fluid requires long-term cell culturing and has a reporting time of c. 10 days to 3 weeks. More rapid results on the most common chromosomal aneuploidies can be achieved by fluorescence in-situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) or quantitative fluorescence-polymerase chain reaction (QF-PCR) testing of uncultured amniotic fluid cells 50,51. However, since array testing can be done on uncultured material, the disparity of reporting times between RAD and array is much smaller than that between RAD and karyotyping. Whether RAD before array testing has an additional value depends highly on local laboratory logistics, local costs and turnaround time of both RAD and array, gestational age and indication. RAD is an important option in pregnancies with a very high risk for common aneuploidies or advanced gestational age if there is a legal time limit for termination of pregnancy. Nevertheless, the fact that patients might be falsely reassured by preliminary normal RAD results should also be taken into account 52,53. Also, one can dispute whether a patient still benefits from RAD if array is not performed simultaneously, as this may delay the final array report. Array testing is now generally accepted in cases of fetal ultrasound anomalies 2 due to its numerous
4 366 Srebniak et al. Table 3 Advantages and disadvantages of whole-genome prenatal microarray as stand-alone test when compared with karyotyping Advantages Higher diagnostic yield: 3% of cases, regardless of referral indication 57 ; 9% of cases with multiple ultrasound anomalies 59 ; 5.6% of cases with isolated ultrasound anomalies 59 ; 0.5 2% in cases without ultrasound anomalies 3,48,58,73. Not dependent on cell culturing (possible on uncultured material). Quality and resolution independent of environmental conditions (contrary to in cell culturing, metaphase harvesting and chromosome staining). Shorter reporting time. Easier to automate; high throughput possible. Chance of undetected low-level mosaicism likely to be smaller than that with conventional karyotyping 15,51,115,126,127. Gene content of the unbalanced anomaly is known immediately and genotype phenotype correlations are facilitated directly. Disadvantages VOUS, variants of unknown clinical significance. The higher the resolution (probe density), the higher the risk of VOUS and unexpected diagnoses. However, current software allows filtering of results, so that some unexpected diagnoses and VOUS (if defined) can be avoided 125. Susceptibility loci for neurodevelopmental disorders are common findings and require proper pre- and post-test counseling. Balanced chromosomal aberrations cannot be detected and prenatal diagnosis in cases of familial balanced aberrations has to be supplemented with karyotyping. advantages when compared to karyotyping (Table 3). However, neither karyotyping nor FISH can disappear from cytogenetic laboratories, as these are important tools in identification of the chromosomal location of CNVs and prediction of the recurrence risk (Table 4) 9. It is likely that karyotyping and metaphase FISH will be used as targeted techniques to answer specific questions arising from abnormal array (or RAD) results. Moreover, since array can only detect unbalanced chromosomal aberrations, karyotyping should be applied if a balanced chromosomal abnormality requires investigation. Indications for prenatal array and testing resolution Fetus with ultrasound anomalies The first cases selected for genome-wide array diagnosis were fetuses with ultrasound anomalies, as it is known that these carry the highest percentage not only of microscopically visible chromosomal abnormalities 54 56, but also of submicroscopic chromosomal aberrations. There is sufficient evidence to support that, in the case of fetal ultrasound anomalies, genomic microarray testing rather than karyotyping should be the gold standard 10,18,48,49,57 59 and this has been recommended Table 4 Indications for karyotyping in material obtained invasively 1. Trisomy 13 or 21 detected by RAD/NIPT or array testing, in order to differentiate between heritable and non-heritable Down and Patau syndrome. 2. In case of normal array result, when one parent is a carrier of a balanced chromosomal aberration, in order to investigate whether the fetus inherited the familial chromosomal aberration. 3. In case of abnormal array results, to specify the chromosomal abnormality (e.g. duplication, insertion, marker chromosome, unbalanced translocation) 9 and recurrence risk. In case of submicroscopic aberrations, metaphase FISH should be used. FISH, fluorescence in-situ hybridization; NIPT, non-invasive prenatal testing; RAD, rapid aneuploidy detection. recently in the prenatal setting 2. The incidence of submicroscopic abnormalities seems to be dependent on the cohort selection as well as on the array resolution 59. In general, about % of fetuses with a structural ultrasound anomaly restricted to one anatomical system and a normal karyotype will show a submicroscopic CNV that explains the phenotype and provides information for fetal prognosis 59. A minimum analysis resolution of 0.4 Mb in cases of affected individuals has already been recommended by the ACMG 41 and this could also be applied in prenatal diagnosis. However, they advise a higher probe density in known pathogenic regions; thus, in the case of a whole-genome array, a resolution of Mb would be advisable 38,39. Intrauterine fetal death (IUFD) It is well known that unbalanced chromosomal abnormalities have been observed in about half of spontaneous miscarriages and in a significant percentage of stillbirths (6 13%) 60. Several studies have shown that, when compared with karyotyping, microarray technology increases the diagnostic yield in cases of intrauterine fetal death (IUFD) or stillbirth A recent study by Reddy et al. 64, in a cohort of 532 cases of stillbirth, showed the additional value of array testing: as compared with karyotyping, array testing provided a relative increase in the diagnosis of genetic abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths and 53.8% in stillbirths with anomalies. Since culture failures due to no cell growth or maternal cell contamination are well-known problems in cases of IUFD 65,66, more successful diagnoses can be achieved by using a SNP array on uncultured material instead of karyotyping. High-resolution (similar to postnatal settings) whole-genome testing would be advisable over targeted testing by QF-PCR or MLPA, but the referring clinicians should be aware that the quality of the DNA from IUFD samples might be relatively low, allowing analysis only at a lower resolution (e.g. 0.5 Mb or 1 Mb) (own experience, especially in macerated tissue). However, even in cases with low-quality DNA, such an approach still enables analysis with a higher resolution than is possible with karyotyping and overcomes culture
5 Editorial 367 failure. Furthermore, to avoid low-quality analysis and failure in postpartum material, performing amniocentesis or chorionic villi sampling in cases of IUFD has already been advised 67. Balanced chromosomal aberration in one of the parents When it is known that one of the parents has a balanced chromosomal aberration, prenatal karyotyping is offered routinely; however, submicroscopic genomic CNVs are an important cause of abnormal phenotypes in carriers of microscopically balanced chromosomal aberrations. A cryptic causative CNV was detected by an array technique in 30 50% of patients with intellectual disability and apparently balanced chromosomal aberrations 68,69. Moreover, Schluth-Bolard and colleagues 70 have reported that genomic imbalances were identified not only in 48.5% of phenotypically abnormal cases with a de novo apparently balanced chromosomal aberration, but also in 28% of patients with intellectual disability and an inherited microscopic balanced chromosomal aberration. To be able to calculate the prevalence of submicroscopic pathogenic CNVs in fetuses of familial balanced chromosomal aberration carriers, more published data from large prenatal cohorts are necessary, as the postnatal cohorts are highly biased. However, only very few prenatal cases have been published. In large prenatal cohorts, carriers of a balanced chromosomal aberration are not evaluated in detail 17,26,42,48,58. Most authors present such patients within unspecified indication subgroups (e.g. family history or others ). Although the cohort of Shaffer et al. 71 was, to our knowledge, the largest to date, they tested only 62 fetuses of a parent with a chromosomal aberration and in 53% an imbalance associated with the familial chromosomal aberration was found. This seems to be a very high incidence of unbalanced karyotype, but the authors did not specify whether the imbalances were products of malsegregation or whether there were also microdeletions at one of the breakpoints found, or how many balanced insertions were investigated. Also, there were no details on whether ultrasound anomalies were seen in these pregnancies. One must keep in mind that fetal phenotypes cannot be investigated fully and it has already been suggested that array diagnostics should not be performed exclusively in cases of fetal ultrasound anomalies 10. Therefore, testing with array, and subsequently with karyotyping if the array shows normal results, might be optimal in cases with familial balanced chromosomal aberrations. High risk for aneuploidy due to advanced maternal age or abnormal first-trimester screening test outcome (with nuchal translucency < 3.5 mm) Although patients with a high risk for aneuploidy due to advanced maternal age or abnormal first-trimester screening test outcome (without fetal structural abnormality or nuchal translucency > 3.5 mm) are nowadays often offered non-invasive prenatal testing (NIPT), patients seeking rapid, reliable and high-resolution diagnostics (rather than a screening test) benefit from invasive prenatal array testing. It has been shown recently by several authors 3,26,48,58,72,73 that a pathogenic submicroscopic abnormality is found in 0.5 2% of uneventful pregnancies. The prevalence of submicroscopic pathogenic findings is sufficiently high as to justify invasive sampling. Moreover, several microdeletion syndromes have a similar prevalence to that of trisomy 13, which is recognized as common and included in RAD or NIPT: for example, 22q11 deletion, with a birth prevalence of c. 1: ,75 and 1p36 deletion, with a birth prevalence of c. 1: , while trisomy 13 occurs in 1:5000 newborns 77.Moreover, there is a general background risk of pathogenic severe submicroscopic chromosomal aberrations of more than 1: It can be disputed that, when patients opt for an invasive diagnostic procedure because of an increased risk of Down syndrome, array testing is preferable to karyotyping or standalone RAD in order to exclude/detect more unbalanced chromosomal aberrations 38, especially since many submicroscopic abnormalities cause intellectual disability and/or anomalies not detectable by fetal ultrasound examination. In other words, are patients only interested in knowledge about fetal Down syndrome or do they also want to be informed about other severe diseases affecting their child? The discussion regarding choice of broad or targeted diagnostics is not a new issue in prenatal diagnosis 78. Boormans and colleagues 79 found in a prospective study that most pregnant women chose broader testing (karyotyping instead of standalone RAD) and recently van der Steen et al. 80 found that if invasive testing is being performed, most patients prefer higher-resolution (0.5 Mb) array testing over that with a resolution of 5 Mb (comparable to karyotyping). Parental anxiety Parental anxiety, a so-called social indication for prenatal genetic testing, is rarely a reason for referral in The Netherlands, but it is commonly in other countries 3,26,71. Fiorentino et al. 3 tested one of the largest cohorts with this indication and detected 11/1675 (0.7%) cases with a pathogenic submicroscopic CNV, similar to the diagnostic yield in patients with advanced maternal age in their cohort. In such cases, array testing can offer more reassurance than can karyotyping; however, the parents should receive extensive pretest counseling, as some of the array results (VOUS, if reported, SL or unexpected diagnoses) may lead to further anxiety. Family history In cases in which there is a family history of congenital anomalies or intellectual disability/developmental delay, it is best practice to test the index patient prior to invasive fetal sampling, as there may be no indication for array testing in the current pregnancy. Sometimes
6 368 Srebniak et al. this is not possible due to the advanced gestational age, in which case simultaneous testing of the index patient and the fetus as well as parental karyotyping might be considered. However, when DNA of the index patient is not available, high-resolution testing of the fetus may be considered if there is also another reason for invasive prenatal testing. In one of the largest cohorts, Shaffer and colleagues 71 detected 15/461 (3.1%) cases with a significant CNV among patients referred due to a family history, while Wapner et al. 58 found only 2/372 (0.5%) patients with a pathogenic CNV. Apparently, such cohorts are highly heterogeneous and their selection determines the frequency of pathogenic findings. Carriers of single gene mutations Carriers of single gene mutations may be offered invasive prenatal testing if the mutation is known and reliable prenatal testing is available. Although most cases represent pregnancies without ultrasound anomalies, there is still the c. 1:200 general population risk for a submicroscopic clinically significant chromosomal abnormality 3,48,58,71. Once the miscarriage risk of the invasive sampling procedure has been accepted, a SNP array (with minimum 0.5-Mb resolution) should be considered 38, although it has been suggested that standalone RAD would be sufficient for such an indication 81. Pretest counseling and reporting to patients With the introduction of prenatal whole-genome array testing, it was anticipated that, compared with karyotyping, there would be a higher frequency of genetic findings that are difficult to interpret and of diagnoses of late-onset (un)treatable disorders not related to the initial referral indication 12. Therefore, pretest genetic counseling was implemented as an obligatory element of microarray testing during pregnancy, as is reflected in recent publications 18,19,21,27 29,33,82 85 and clinical guidelines 41. Most publications recommend that pretest counseling should be carried out by a genetic specialist. A few papers do not specify whether the counseling was done by a clinical geneticist or other medical specialist 3,86 and a few state that the pretest counseling was done by ultrasound specialists 26,32. Routine application of array prenatal testing can lead to increasing numbers of patients choosing prenatal array without there being sufficient numbers of medical doctors specialized in clinical genetics available for pretest counseling. Genetic counselors/nurses and gynecologists/ultrasonographers should therefore be trained in the complexities of array pretest counseling, thus allowing the clinical geneticists to focus on complex cases 87. This new approach seems to have been adapted by Scott and colleagues 26 and is used by our group (in prep.); in both cases all patients receive pretest counseling by ultrasound specialists or gynecologists, allowing more than 1000 arrays to be performed per year. Unfortunately, almost none of the publications specifies the issues addressed during pretest counseling and only a few reports mention that the patients were given a choice regarding findings about which they wished to be informed 21,32. Problematic array findings Unexpected diagnoses In addition to pathogenic causative array findings (fitting the referral reason), so-called unexpected diagnoses can also be made 88. Pathogenic findings that do not match the indication for testing or the fetal phenotype seen on ultrasound have always accompanied whole-genome cytogenetic testing 89 ; however, because array testing has a higher diagnostic yield, they are found more frequently. Interpretation of array findings is also more complex in a prenatal setting than it is in a postnatal setting due to the fact that the prenatal phenotype is only described by ultrasound imaging and cannot be investigated fully. It is not always possible to assess whether the pathogenic CNV explains the fetal phenotype. Therefore, it is not always easy to distinguish a causative array finding from an unexpected diagnosis. Subsequent (targeted) ultrasound examination, autopsy or postnatal examination and follow-up may reveal additional abnormalities that may match the fetal genotype. Due to this limitation, it is difficult to determine the actual ratio between clearly pathogenic causative findings and unexpected diagnoses in prenatal settings. Unexpected diagnoses of early-onset severe diseases may be an additional value of prenatal array testing if invasive sampling is performed. Unfortunately, very few publications discuss unexpected prenatal diagnoses at all 73, and the few that do so mention only late-onset diseases 18,32,59. The terminology of array findings can be problematic as a result of unclear definitions. This is underlined by the term incidental finding : many authors classify some prenatally discovered CNVs as incidental findings without defining the term 18,25,90 and others simply include such findings in one group of clinically significant array findings 17. To facilitate counseling, a more detailed classification of pathogenic array findings would be useful 88. If patients are supposed to choose predetermined types of findings about which they wish to be informed and to understand the possible outcomes, a clear classification with illustrative examples should be given during pretest counseling. Pathogenic unexpected array findings may be subdivided into four subcategories: early-onset untreatable diseases, early-onset treatable diseases, late-onset untreatable diseases and late-onset treatable diseases. There is no international consensus on what kind of unexpected diagnoses in fetuses and incidental findings in parental samples should be reported, and we should exercise caution in the case of every late-onset (un)treatable disease. What should be reported seems to depend mainly on condition-specific factors such as disease severity, age at onset, treatment availability and evidence indicating pathogenicity 40,91. Guidelines suggesting release of all unexpected diagnoses to patients
7 Editorial 369 and recommending a minimum list of genes that should be investigated have been published 92. However, in prenatal and pediatric settings, this may lead to severe ethical and psychosocial implications 93, especially because some findings may lead to future discrimination of individuals known to carry late-onset diseases (both treatable and untreatable), and thereby undermine the child s rights The decision to report or not to report seems to be highly individual and the majority ( 80%) of genetic counselors and geneticists believe that the parents should be given a choice as to what kinds of unexpected diagnoses are returned to them 91, after extensive pretest (or even preconception) counseling 96. Since many genetic diseases are very rare, an appropriate balance between informing about all possibilities and preventing unnecessary anxiety in the future parents has to be found 32. Susceptibility loci (SL) for neurodevelopmental disorders CNVs associated with incomplete penetrance, variable expressivity and heterogeneity of clinical features (e.g. 16p11.2 microdeletion or 22q11 microduplication; so-called SL for neurodevelopmental disorders) may complicate post-test counseling, if reported, and may complicate classification of array findings. Although there are guidelines 45,97, and such findings may be classified as pathogenic 88, some classify such CNVs as VOUS 33,58. The phenotypes of SL carriers seems to vary from normal to severely affected and the phenotypes of control individuals carrying SL were shown recently to be intermediate between affected carriers and non-carrier control individuals 98, so the presence of an abnormal phenotype seems to be dependent on a second hit 99. Nevertheless, the classification of such findings seems to be controversial and there is no internationally recognized policy regarding whether to report them. These SLs, variants associated with neurodevelopmental disorders, but of extreme phenotypic heterogeneity and/or variable expressivity, are quite often found in the prenatal setting. Data in the literature show a statistically significantly higher frequency of SL in fetuses with ultrasound abnormalities when compared with those without: 3.6% vs 0.8% 58 and 1.4% vs 0.55% 26. The exact risk for developing a specific disease/phenotype, if such a finding is discovered prenatally, is still largely unquantifiable 100,101 and therefore the prognosis for the fetus is unsure. Some of the SL involve a structural abnormality (e.g. heart anomaly in 1q21.1 duplication), so an ultrasound investigation should be offered 33. When there is an increased likelihood of neurodevelopmental disorder, a medical follow-up may be advised to assure early intervention if needed. Both reporting and classification of SL might be questionable, but these are relatively frequent findings and they should be further investigated. There should be long-term follow-up of cases ascertained prenatally, to provide more insight into the as yet unquantifiable risk for an abnormal phenotype when a SL is detected prenatally in an uneventful pregnancy in an apparently healthy family, as postnatal studies may be biased. VOUS The question as to what to report becomes even more complicated when it concerns VOUS. In the literature there is no consensus at all in (sub)classifying and reporting VOUS. For example, some researchers classify inherited VOUS as likely benign 102. Maya et al. 103 divided CNVs into only two categories: highly clinically significant (likely to be causal), and benign, but both types of CNVs were reported to patients. Although some guidelines and recommendations are available 41,97,104, the interpretation of array data remains complex 105 and there is a certain gray area, between potentially pathogenic VOUS and truly pathogenic findings, that is caused by limited knowledge and the rarity of genetic diseases. Most of the recent publications mentioned in this Editorial show that at least some VOUS are reported; however, there are different conditions for reporting. Some report all VOUS 29, others report only actionable VOUS 33 and others report VOUS after multidisciplinary decisions 58. Some authors strongly recommend only reporting pathogenic array findings in the prenatal setting 21,33,40,106. Reporting CNVs classified as benign or polymorphic, and reporting true VOUS, from which the causality is often overestimated (even if de novo) 107, does not affect pregnancy management. Yet, if reported, these findings may complicate the decision as to whether to continue or terminate the pregnancy (illustrated by the example described by Charan et al. 108 ). Bernhardt and colleagues 52,109 described some women to whom uncertain results were given and who continued to worry after delivery, regretting having the test. Most patients did not even recall discussing VOUS during pretest counseling and many were falsely reassured by normal preliminary results (RAD and karyotyping). Moreover, Lohn et al. 91 showed that some of the patients with a VOUS actually believed that a pathogenic CNV had been found in their child. Therefore, there should be careful consideration in a multidisciplinary setting as to whether a VOUS is potentially pathogenic and worth reporting (actionable) 58. Conclusions and future perspectives In our opinion, it is only a matter of time until rapid SNP array testing with reporting within 1 week will be a first-tier routine cytogenetic prenatal test for all indications. We advocate, based on the literature and on our own experience, that the advantages of using whole-genome array as a first-tier diagnostic prenatal test largely outweigh the disadvantages. Therefore, we should discuss not whether to implement array, but rather how to deal with the difficulties: how to improve the classification and interpretation of findings and how to achieve consensus in reporting VOUS, SL and late-onset (un)treatable disorders if encountered unexpectedly. It is the responsibility of all specialists in clinical genetics to ensure detection of pathogenic findings without violating patients (and their future children s) autonomy and their right not to know, and without causing future stigma and discrimination. We are only one step away
8 370 Srebniak et al. from next-generation sequencing in prenatal clinics 110. Through massively parallel sequencing, non-invasive prenatal diagnosis of trisomies 111 and microdeletions 112, as well as sequencing of the whole fetal genome 113,is already technically possible 114. If these techniques become cheaper and more robust, we can expect that they will be implemented into routine clinical practice. To ensure rapid management of enormous amounts of genomic variants in clinical practice, a clear strategy is essential. Knowledge of the technical, interpretational, ethical and psychological challenges in prenatal array testing will be indispensable in the near future. In order to guarantee responsible and balanced patient care, we will need experienced clinical geneticists to be able to communicate complex results. We should, therefore, start discussing now the challenges of prenatal whole-genome sequencing (for both CNV and mutation analysis), so we are prepared for detecting both CNV and mutations in a non-invasive setting (in maternal plasma) in affected and unaffected pregnancies. REFERENCES 1. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86: ACOG Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. 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Eur J Hum Genet 2011; 19: Wapner RJ, Driscoll DA, Simpson JL. Integration of microarray technology into prenatal diagnosis: counselling issues generated during the NICHD clinical trial. Prenat Diagn 2012; 32: Koolen DA, Sistermans EA, Nilessen W, Knight SJ, Regan R, Liu YT, Kooy RF, Rooms L, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, van Kessel AG, Nordenskjold M, de Vries BB. Identification of non-recurrent submicroscopic genome imbalances: the advantage of genome-wide microarrays over targeted approaches. Eur J Hum Genet 2008; 16: Charan P, Woodrow N, Walker SP, Ganesamoorthy D, McGillivray G, Palma-Dias R. High-resolution microarray in the assessment of fetal anomalies detected by ultrasound. Aust N Z J Obstet Gynaecol 2014; 54: Vestergaard EM, Christensen R, Petersen OB, Vogel I. Prenatal diagnosis: array comparative genomic hybridization in fetuses with abnormal sonographic findings. Acta Obstet Gynecol Scand 2013; 92: Scott F, Murphy K, Carey L, Greville W, Mansfield N, Barahona P, Robertson R, McLennan A. Prenatal diagnosis using combined quantitative fluorescent polymerase chain reaction and array comparative genomic hybridization analysis as a first-line test: results from over 1000 consecutive cases. Ultrasound Obstet Gynecol 2013; 41: Schmid M, Stary S, Springer S, Bettelheim D, Husslein P, Streubel B. Prenatal microarray analysis as second-tier diagnostic test: single-center prospective study. Ultrasound Obstet Gynecol 2013; 41: Rooryck C, Toutain J, Cailley D, Bouron J, Horovitz J, Lacombe D, Arveiler B, Saura R. Prenatal diagnosis using array-cgh: A French experience. EurJMed Genet 2013; 56: Ganesamoorthy D, Bruno DL, McGillivray G, Norris F, White SM, Adroub S, Amor DJ, Yeung A, Oertel R, Pertile MD, Ngo C, Arvaj AR, Walker S, Charan P, Palma-Dias R, Woodrow N, Slater HR. Meeting the challenge of interpreting high-resolution single nucleotide polymorphism array data in prenatal diagnosis: does increased diagnostic power outweigh the dilemma of rare variants? BJOG 2013; 120: Liao C, Li R, Fu F, Xie G, Zhang Y, Pan M, Li J, Li D. Prenatal diagnosis of congenital heart defect by genome-wide high-resolution SNP array. Prenat Diagn 2014; 34: Oneda B, Baldinger R, Reissmann R, Reshetnikova I, Krejci P, Masood R, Ochsenbein-Kolble N, Bartholdi D, Steindl K, Morotti D, Faranda M, Baumer A, Asadollahi R, Joset P, Niedrist D, Breymann C, Hebisch G, Husler M, Mueller R, Prentl E, Wisser J, Zimmermann R, Rauch A. High-resolution chromosomal microarrays in prenatal diagnosis significantly increase diagnostic power. Prenat Diagn 2014; 34: Faas BH, Feenstra I, Eggink AJ, Kooper AJ, Pfundt R, van Vugt JM, de Leeuw N. Non-targeted whole genome 250 K SNP array analysis as replacement for karyotyping in fetuses with structural ultrasound anomalies: evaluation of a one-year experience. Prenat Diagn 2012; 32: Brady PD, Delle Chiaie B, Christenhusz G, Dierickx K, Van Den Bogaert K, Menten B, Janssens S, Defoort P, Roets E, Sleurs E, Keymolen K, De Catte L, Deprest J, de Ravel T, Van Esch H, Fryns JP, Devriendt K, Vermeesch JR. A prospective study of the clinical utility of prenatal chromosomal microarray analysis in fetuses with ultrasound abnormalities and an exploration of a framework for reporting unclassified variants and risk factors. Genet Med 2014; 16: Hillman SC, McMullan DJ, Silcock L, Maher ER, Kilby MD. How does altering the resolution of chromosomal microarray analysis in the prenatal setting affect the rates of pathological and uncertain findings? J Matern Fetal Neonatal Med 2014; 27: Association for Clinical Cytogenetics. 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