DOI: 10.1002/pd.4531
PRESENTATION FROM THE 2014 ISPD MEETING IN BRISBANE, AUSTRALIA
Current controversies in prenatal diagnosis 3: the ethical and counseling implications of new genomic technologies: all pregnant women should be offered prenatal diagnostic genome-wide testing for prenatally identified fetal congenital anomalies† R. Douglas Wilson1‡, David H. Ledbetter2‡ and Eugene Pergament3‡ 1
Cummings School of Medicine University of Calgary, Calgary, Alberta, Canada Geisinger Health System, Danville, PA, USA 3 Northwestern School of Medicine, Chicago, IL, USA *Correspondence to: R. Douglas Wilson. E-mail: [email protected] † This written debate summarizes the oral presentation made at the 2014 International Society for Prenatal Diagnosis meeting in Brisbane, Australia. It does not necessarily reflect the personal opinions of each of the authors. ‡ All authors contributed equally to this work. 2
Funding sources: None Conflicts of interest: None declared
INTRODUCTION (R. D. WILSON) First and second trimester imaging for all pregnancies is a wellrecognized “standard of care”. The natural prevalence for fetal anomalies is estimated at 5% (1 in 20 live born infants), but it is higher in monochorionic twins, secondary to the monochorionic twinning process. Sonographic imaging will identify the majority of major “structural” anomalies that account for approximately 70% of the congenital burden. The terminologies for the congenital anomalies in morphogenesis that may have genetic etiologies are1: Malformation— localized errors/poor formation Dysplasia— abnormal cellular organization in the tissue Malformations can be single or multiple and can be organized into syndromes, sequences,"" and associations. Dysplasia can be single or multiple but are usually only in sequences.2 The ethics and counseling processes are more complex with the new molecular prenatal testing options. The issues of how to preserve the reproductive autonomy, how to ensure informed consent, and how to respect the autonomy of the future child if late onset disease prediction occurs are complex.3,4 Other factors for consideration are that molecular karyotyping using chromosomal microarray analysis will detect more pathogenic chromosomal anomalies than standard karyotyping. NICHD investigators reported the evaluation of this genomic technology with fetal anomalies. Of the 1082 fetuses with anomalies, 752 had a normal karyotype. The microarray analysis identified additional chromosomal abnormalities (pathogenic copy number variants (CNVs)) in 8.1% of cases, and if there were more than one anatomical system involved the result was 13%.5 Prenatal Diagnosis 2015, 35, 19–22
The recommendation for debate is:
With the recognized ethical and counseling implications of the new genomic technologies, all pregnant women should be offered prenatal diagnostic genomewide testing when prenatal ultrasound screening identifies the presence of fetal congenital anomalies (isolated; multiple; major; minor)
SUPPORTING THE RECOMMENDATION (D. H. LEDBETTER) As a clinical cytogeneticist, I take the position that genome-wide testing has been the standard in prenatal diagnosis since the first karyotype analysis after amniocentesis. The G-banded karyotype has a resolution of ~5–10 Mb in a prenatal setting, and essentially all visible deletions or duplications are associated with intellectual disability (ID) accompanied by variable physical medical problems depending on the genes involved. So, the debate is not really whether genome-wide prenatal testing should be offered, but at what level of resolution. The higher the resolution, the greater the sensitivity for detection of microdeletions and microduplications (now referred to as copy number variants or CNVs). However, the trade-off for increased sensitivity is an increased rate of CNVs for which we do not currently know their clinical significance—called variants of uncertain significance or VOUS. Whole-genome chromosomal microarray analysis (CMA) increased the yield of pathogenic imbalances in children with unexplained developmental delay/ID, autism spectrum disorders (ASD) as well as those with multiple congenital anomalies to © 2014 John Wiley & Sons, Ltd.
20
15–20% and is now recommended as the first-line genetic test for this population.6,7 A multi-center trial of CMA in a prenatal setting demonstrated an additional 2.5% yield of clinically significant findings compared to karyotype, varying from 6% in pregnancies with ultrasound anomalies to 1.7% in AMA or positive screen pregnancies without ultrasound findings.8 Importantly, among AMA and positive screen pregnancies, 1 in 125 showed a pathogenic CNV associated with cognitive impairment and psychiatric disorders.8 Since these CNVs are not associated with maternal age or screen-positive status, this result suggests that all pregnancies are at 1 in 125 risk for these disorders—i.e. there is no such thing as a low-risk pregnancy! The downside of this increased resolution is a corresponding increase in the rate of VOUS. In the NICHD multicenter study,8 the rate of VOUS at the beginning of the study was 2.5%, but by its conclusion in 2012 had dropped to 1.5% or less. This percentage will be dependent upon each laboratory’s reporting practices, with some laboratories over-reporting variants that do not have any evidence of clinical significance as a conservative or even defensive strategy. A feature of CNV disorders is the variability in clinical presentation, from severely to mildly affected or “apparently normal”. Similar clinical variability is observed for many genetic conditions and raises the question of incomplete penetrance. As discussed elsewhere,9 this clinical variability is best viewed as dimensional traits (e.g. IQ, social cognition, etc.) that are normally distributed in the general population. Presence of a CNV often “shifts” this distribution in a deleterious direction by 1–2 standard deviations but retains a broad distribution around the new mean. Just like older literature demonstrating that the tallest individuals with Turner syndrome are the offspring of the tallest parents, and the highest functioning Down syndrome or Prader–Willi syndrome individuals are the offspring of parents with the highest IQ scores, the cognitive and social functioning of children with a CNV correlates significantly with the performance level of their parents.10 Thus, family background, including genetic and environmental contributions, can influence the clinical variability in a child with a CNV. More data are needed to improve our understanding of the clinical consequences of CNVs. There are several efforts aimed at gathering larger datasets of clinical data combined with structural and sequence variants in the human genome. One of these major efforts is ClinGen, the Clinical Genome Resource Project funded by the National Human Genome Research Institute (http://www.clinicalgenome.org), the goal of which is to develop a clinician-friendly resource of evidence-based information on the clinical significance of human variants. A less biased ascertainment of CNVs would be those identified prenatally in which the pregnancy continues to term and followup clinical data obtained. Such a prenatal project is currently being conducted as a follow-up to the NICHD prenatal array study and is actively seeking case referrals (www.prenatalarray.org). What is the ultimate goal of applying whole genome analysis prenatally? There are recent data suggesting that early detection of some CNVs and other chromosomal abnormalities allow early intervention that improves developmental outcomes. Cheung et al.11 suggested that early recognition (including prenatal) of the microdeletion 22q11.2 in DiGeorge syndrome may allow early treatment of neonatal hypocalcemia to avoid the onset of Prenatal Diagnosis 2015, 35, 19–22
R. D. Wilson et al.
seizures resulting in improved long-term cognitive outcomes. Samango-Sprouse et al.12 published retrospective data on XXY males with early androgen treatment that correlated with improved language, intellectual, and neuromotor function. These examples could be the vanguard of a new paradigm in prenatal diagnosis aimed at intervention and treatment rather than providing limited options regarding reproductive decisions.
AGAINST THE RECOMMENDATION (E. PERGAMENT) The proposition that all women should be offered genome-wide testing for congenital anomalies is rejected primarily on the basis that potential harms outweigh potential benefits. While it is accepted that access to genomic information is ultimately a pregnant woman’s prerogative, health professionals have the medical responsibility of minimizing harm, ensuring appropriate pre test and post test information, providing truly informed consent, conducting laboratory testing of high quality, and guaranteeing confidentiality of all personal data. It is also recognized that a pregnant woman’s decision concerning genome-wide testing will likely be influenced by a broad range of external forces including her partner as well as medical societies, insurance companies, governmental agencies, and her healthcare provider. For the latter, the major overriding, critical concern is that a pregnant woman’s decision is based on complete understanding of the benefits and risks of genome-wide testing. And, as a precondition of genome-wide testing, two factors must be considered: (i), whether such testing has clinical validity and (ii) there is reasonable potential use of the information. Genome-wide testing fails on the basis of both preconditions. A major criticism of the current status of genome-wide testing is that results are not necessarily clear-cut and information about their clinical consequences has not been well established. In turn, uncertainty will invariably lead to misunderstanding, either an overestimation or an underestimation of the developmental effects of test results. From a genetic counseling perspective, what has yet to be established is the exact information to be communicated to a pregnant patient before and after testing and who are to be the providers of information. Applying genome-wide testing for all women generates an unprecedented challenge to healthcare providers to secure informed consent, particularly since professional standards have not been established, nor have the limitations, risks, and implications of genome-wide testing been adequately defined. What has yet to be established by the medical community is what genome information is to be provided the pregnant woman? For example, beyond medical testing, does the genome-wide data include predisposition to late-onset disease, susceptibility to certain infectious disorders, or sensitivity to certain chemicals and foods? At this point in time, the aims and motivations of genomic testing appear ill-defined and not clearly stated, thereby compromising clinical validity and unresolved question of utility. If adequate pre test and post test counseling cannot be ensured, if informed consent cannot be ensured, and if the reliability of test results cannot be ensured, that all women should be offered genome-wide testing for congenital anomalies must be rejected on the basis of its ethical and counseling implications. © 2014 John Wiley & Sons, Ltd.
Plenary debate session: controversies in prenatal diagnosis 3
What then, is the underlying consequence of genome-wide testing for all women, given the present state of knowledge? What currently is in practice is uncertainty of the meaning of genomewide test results in many instances, an unpredictability concerning the penetrance and expressivity of a wide spectrum of genomic changes at the submicroscopic level, and an accompanying lack of precise genotype–phenotype correlation. What is not in place are the components necessary to assure the integrity of a pregnant woman’s decision-making whether to undergo fetal genome-wide testing. This includes the formal education of practitioners and counselors concerning the science of interpretation of genomic information as well as established approaches dealing with uncertainty; the composition of healthcare providers interpreting genome-wide testing results to a pregnant woman; uniform and standardized guidelines by professional and governmental organizations; detailed knowledge of pregnant women’s attitudes and desires; and, complete understanding and knowledge of genotype–phenotype correlations based on in utero (as opposed to postnatal) expression. The wide variable expression associated with 22q11.2, both physically and intellectually, dramatizes the counseling dilemma generated by genome-wide testing of all women. When intelligence scores in this instance range from a low of 60 to a high approaching 100, it has yet to be specifically established what and how this information is to be communicated. It would appear that this circumstance is reminiscent of a time when no prenatal genetic testing was available and pregnant women could only be given odds. When women experience abnormal genomic results, these are their responses: “an offer too good to pass up,” “blindsided by the results,” “uncertainty and unquantifiable risks,” “need for support,” and, most telling, “toxic knowledge ”.13
CONCLUSIONS (BASED ON THE PRESENTATIONS AND THE DISCUSSION PERIOD WITH THE PRESENTERS AND THE AUDIENCE) 1. The audience consensus, polled prior to the debate by a “show of hands” indicated a 60–65% support for the recommendation of genome-wide testing when there is prenatal identification of congenital anomalies by the screening ultrasound test.
2. Following the debate and discussion, the audience consensus had reversed their support for the recommendation as there was a great amount of discussion related to: 2.1 The present but variable process for patient education and genetic understanding of the genomic technology; 2.2 The requirement that “true” maternal informed consent was required considering the benefits and risks of the fetal genomic information and the recognition that the prenatal diagnosis technique (chorionic villus sampling (CVS);
21
amniocentesis (A)) required to undertake the genomic fetal testing had a risk of pregnancy loss estimated at 0.5–1.0%; 2.3 The audience’s opinion indicated that the genetic counseling/ knowledge translation systems varied internationally and that if the recommendation was to be implemented, a welldesigned system of informed consent with pre and post testing support was required along with well-defined laboratory and genetic reporting standards. The counseling time and the genetic human resource implications for this recommendation and the implementation process were discussed. 2.4 The discussion between presenters and the audience, related to specific mutations with childhood cognitive morbidity, was interactive and passionately argued by supporters and non-supporters of the recommendation. 2.5 The option for prenatal or postnatal therapy directed at improved childhood outcomes is a compelling argument, but this aspect will require more investigation and follow-up. 3. The final consensus summary is that, while the present genomic diagnostic technology with access to prenatal testing following an informed consent process recommendation would likely become a “future” standard of care for prenatal screening/diagnosis/therapy when specific fetal anomalies/syndromes are identified, the debate recommendation could not be completely supported, at this time, by the international audience attending the 2014 18th ISPD meeting in Brisbane Australia.
ACKNOWLEDGEMENTS The co-author (EP) wishes to acknowledge that his presented and written opinion is based, in part, on the Ph.D Thesis of Eline Bunnick of Rotterdam Erasmus University, Netherlands, “Up close and personal: ethical issues in genetic testing.” 2013 as summarized by Peter Schielen, Ph.D., in Prenatal Perspectives, Volume 2, Number 2, 2014.
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • Congenital anomalies are common in human reproduction and have a prevalence of 5%. • Molecular fetal karyotyping using microarray analysis will detect more pathogenic chromosomal anomalies. • Patient understanding related to the complexity and the information identified with fetal microarray testing is variable and very limited.
WHAT DOES THIS STUDY ADD? • More consistent and in-depth patient counseling is required so that this new technology can be used for higher levels of informed consent, for better diagnostic information, and within an appropriate ethical framework.
REFERENCES 1. Jones KL, Jones MC, del Campo M. Smith’s Recognizable Patterns of Human Malformation (7th edn). Saunders Elsevier: Philadelphia, 2013;1–6. 2. Firth HV, Hurst JA. Oxford Desk Reference Clinical Genetics. Oxford University Press: Oxford, 2005;4–5. 3. Bunnik EM, De Jong A, Nijsingh N, De Wert GMWR. The New Genetics and Informed Consent: Differentiating Choice to Preservers Autonomy. Bioethics 2013;27(6):348–55. 4. McGillivray G, Rosenfeld JA, McKinlay Gardner M, Gillam LH. Genetic counselling and ethical issues with chromosome microarray analysis in prenatal testing. Prenat Diagn 2012;32:389–95.
Prenatal Diagnosis 2015, 35, 19–22
5. Donnelly JC, Platt LD, Rebarber A, et al. Association of Copy Number variants with Specific Ultrasonographically Detected Fetal Anomalies. Obstet Gynecol 2014;124:83–90. 6. Miller DT. Consensus statement on chromosomal microarray as a firsttier clinical diagnostic test for individuals with developmental delay/ intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. Am J Hum Genet 2010;86:749–64. 7. Manning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 2010;12:742–5.
© 2014 John Wiley & Sons, Ltd.
22
8. Wapner, RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012;367:2175–84. 9. Ledbetter DH, Riggs ER, Martin CL. Clinical applications of wholegenome chromosomal microarray analysis. In Genomic and Personalized Medicine (2nd edn). Elsevier: Amsterdam, 2013;133–44. 10. Moreno-De-Luca A. Clinical variability in individuals with 16p11.2 deletions is partially explained by parental cognitive, behavioral and motor profiles. Biol Psychiatry 2014; PII: S0006-3223 (14) 00427-2, doi: 10.1016/j.biopsych.2014.04.021.
Prenatal Diagnosis 2015, 35, 19–22
R. D. Wilson et al.
11. Cheung EN, George SR, Andrade DM, et al. Neonatal hypocalcemia, neonatal seizures, and intellectual disability in 22q11.2 deletion syndrome. Genet Med 2014;16:40–4. 12. Samango-Sprouse CA, Sadeghin T, Mitchell FL, et al. Postive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47,XXY syndrome at 36 and 72 months of age. Am J Med Genet A 2013;161:501–8. 13. Bernhardt BA, Soucier D, Hanson K, et al. Women’s experiences receiving abnormal prenatal chromosomal microarray testing results. Genet Med 2013;15(2):139–45.
© 2014 John Wiley & Sons, Ltd.
PRESENTATION FROM THE 2014 ISPD MEETING IN BRISBANE, AUSTRALIA
Current controversies in prenatal diagnosis 3: the ethical and counseling implications of new genomic technologies: all pregnant women should be offered prenatal diagnostic genome-wide testing for prenatally identified fetal congenital anomalies† R. Douglas Wilson1‡, David H. Ledbetter2‡ and Eugene Pergament3‡ 1
Cummings School of Medicine University of Calgary, Calgary, Alberta, Canada Geisinger Health System, Danville, PA, USA 3 Northwestern School of Medicine, Chicago, IL, USA *Correspondence to: R. Douglas Wilson. E-mail: [email protected] † This written debate summarizes the oral presentation made at the 2014 International Society for Prenatal Diagnosis meeting in Brisbane, Australia. It does not necessarily reflect the personal opinions of each of the authors. ‡ All authors contributed equally to this work. 2
Funding sources: None Conflicts of interest: None declared
INTRODUCTION (R. D. WILSON) First and second trimester imaging for all pregnancies is a wellrecognized “standard of care”. The natural prevalence for fetal anomalies is estimated at 5% (1 in 20 live born infants), but it is higher in monochorionic twins, secondary to the monochorionic twinning process. Sonographic imaging will identify the majority of major “structural” anomalies that account for approximately 70% of the congenital burden. The terminologies for the congenital anomalies in morphogenesis that may have genetic etiologies are1: Malformation— localized errors/poor formation Dysplasia— abnormal cellular organization in the tissue Malformations can be single or multiple and can be organized into syndromes, sequences,"" and associations. Dysplasia can be single or multiple but are usually only in sequences.2 The ethics and counseling processes are more complex with the new molecular prenatal testing options. The issues of how to preserve the reproductive autonomy, how to ensure informed consent, and how to respect the autonomy of the future child if late onset disease prediction occurs are complex.3,4 Other factors for consideration are that molecular karyotyping using chromosomal microarray analysis will detect more pathogenic chromosomal anomalies than standard karyotyping. NICHD investigators reported the evaluation of this genomic technology with fetal anomalies. Of the 1082 fetuses with anomalies, 752 had a normal karyotype. The microarray analysis identified additional chromosomal abnormalities (pathogenic copy number variants (CNVs)) in 8.1% of cases, and if there were more than one anatomical system involved the result was 13%.5 Prenatal Diagnosis 2015, 35, 19–22
The recommendation for debate is:
With the recognized ethical and counseling implications of the new genomic technologies, all pregnant women should be offered prenatal diagnostic genomewide testing when prenatal ultrasound screening identifies the presence of fetal congenital anomalies (isolated; multiple; major; minor)
SUPPORTING THE RECOMMENDATION (D. H. LEDBETTER) As a clinical cytogeneticist, I take the position that genome-wide testing has been the standard in prenatal diagnosis since the first karyotype analysis after amniocentesis. The G-banded karyotype has a resolution of ~5–10 Mb in a prenatal setting, and essentially all visible deletions or duplications are associated with intellectual disability (ID) accompanied by variable physical medical problems depending on the genes involved. So, the debate is not really whether genome-wide prenatal testing should be offered, but at what level of resolution. The higher the resolution, the greater the sensitivity for detection of microdeletions and microduplications (now referred to as copy number variants or CNVs). However, the trade-off for increased sensitivity is an increased rate of CNVs for which we do not currently know their clinical significance—called variants of uncertain significance or VOUS. Whole-genome chromosomal microarray analysis (CMA) increased the yield of pathogenic imbalances in children with unexplained developmental delay/ID, autism spectrum disorders (ASD) as well as those with multiple congenital anomalies to © 2014 John Wiley & Sons, Ltd.
20
15–20% and is now recommended as the first-line genetic test for this population.6,7 A multi-center trial of CMA in a prenatal setting demonstrated an additional 2.5% yield of clinically significant findings compared to karyotype, varying from 6% in pregnancies with ultrasound anomalies to 1.7% in AMA or positive screen pregnancies without ultrasound findings.8 Importantly, among AMA and positive screen pregnancies, 1 in 125 showed a pathogenic CNV associated with cognitive impairment and psychiatric disorders.8 Since these CNVs are not associated with maternal age or screen-positive status, this result suggests that all pregnancies are at 1 in 125 risk for these disorders—i.e. there is no such thing as a low-risk pregnancy! The downside of this increased resolution is a corresponding increase in the rate of VOUS. In the NICHD multicenter study,8 the rate of VOUS at the beginning of the study was 2.5%, but by its conclusion in 2012 had dropped to 1.5% or less. This percentage will be dependent upon each laboratory’s reporting practices, with some laboratories over-reporting variants that do not have any evidence of clinical significance as a conservative or even defensive strategy. A feature of CNV disorders is the variability in clinical presentation, from severely to mildly affected or “apparently normal”. Similar clinical variability is observed for many genetic conditions and raises the question of incomplete penetrance. As discussed elsewhere,9 this clinical variability is best viewed as dimensional traits (e.g. IQ, social cognition, etc.) that are normally distributed in the general population. Presence of a CNV often “shifts” this distribution in a deleterious direction by 1–2 standard deviations but retains a broad distribution around the new mean. Just like older literature demonstrating that the tallest individuals with Turner syndrome are the offspring of the tallest parents, and the highest functioning Down syndrome or Prader–Willi syndrome individuals are the offspring of parents with the highest IQ scores, the cognitive and social functioning of children with a CNV correlates significantly with the performance level of their parents.10 Thus, family background, including genetic and environmental contributions, can influence the clinical variability in a child with a CNV. More data are needed to improve our understanding of the clinical consequences of CNVs. There are several efforts aimed at gathering larger datasets of clinical data combined with structural and sequence variants in the human genome. One of these major efforts is ClinGen, the Clinical Genome Resource Project funded by the National Human Genome Research Institute (http://www.clinicalgenome.org), the goal of which is to develop a clinician-friendly resource of evidence-based information on the clinical significance of human variants. A less biased ascertainment of CNVs would be those identified prenatally in which the pregnancy continues to term and followup clinical data obtained. Such a prenatal project is currently being conducted as a follow-up to the NICHD prenatal array study and is actively seeking case referrals (www.prenatalarray.org). What is the ultimate goal of applying whole genome analysis prenatally? There are recent data suggesting that early detection of some CNVs and other chromosomal abnormalities allow early intervention that improves developmental outcomes. Cheung et al.11 suggested that early recognition (including prenatal) of the microdeletion 22q11.2 in DiGeorge syndrome may allow early treatment of neonatal hypocalcemia to avoid the onset of Prenatal Diagnosis 2015, 35, 19–22
R. D. Wilson et al.
seizures resulting in improved long-term cognitive outcomes. Samango-Sprouse et al.12 published retrospective data on XXY males with early androgen treatment that correlated with improved language, intellectual, and neuromotor function. These examples could be the vanguard of a new paradigm in prenatal diagnosis aimed at intervention and treatment rather than providing limited options regarding reproductive decisions.
AGAINST THE RECOMMENDATION (E. PERGAMENT) The proposition that all women should be offered genome-wide testing for congenital anomalies is rejected primarily on the basis that potential harms outweigh potential benefits. While it is accepted that access to genomic information is ultimately a pregnant woman’s prerogative, health professionals have the medical responsibility of minimizing harm, ensuring appropriate pre test and post test information, providing truly informed consent, conducting laboratory testing of high quality, and guaranteeing confidentiality of all personal data. It is also recognized that a pregnant woman’s decision concerning genome-wide testing will likely be influenced by a broad range of external forces including her partner as well as medical societies, insurance companies, governmental agencies, and her healthcare provider. For the latter, the major overriding, critical concern is that a pregnant woman’s decision is based on complete understanding of the benefits and risks of genome-wide testing. And, as a precondition of genome-wide testing, two factors must be considered: (i), whether such testing has clinical validity and (ii) there is reasonable potential use of the information. Genome-wide testing fails on the basis of both preconditions. A major criticism of the current status of genome-wide testing is that results are not necessarily clear-cut and information about their clinical consequences has not been well established. In turn, uncertainty will invariably lead to misunderstanding, either an overestimation or an underestimation of the developmental effects of test results. From a genetic counseling perspective, what has yet to be established is the exact information to be communicated to a pregnant patient before and after testing and who are to be the providers of information. Applying genome-wide testing for all women generates an unprecedented challenge to healthcare providers to secure informed consent, particularly since professional standards have not been established, nor have the limitations, risks, and implications of genome-wide testing been adequately defined. What has yet to be established by the medical community is what genome information is to be provided the pregnant woman? For example, beyond medical testing, does the genome-wide data include predisposition to late-onset disease, susceptibility to certain infectious disorders, or sensitivity to certain chemicals and foods? At this point in time, the aims and motivations of genomic testing appear ill-defined and not clearly stated, thereby compromising clinical validity and unresolved question of utility. If adequate pre test and post test counseling cannot be ensured, if informed consent cannot be ensured, and if the reliability of test results cannot be ensured, that all women should be offered genome-wide testing for congenital anomalies must be rejected on the basis of its ethical and counseling implications. © 2014 John Wiley & Sons, Ltd.
Plenary debate session: controversies in prenatal diagnosis 3
What then, is the underlying consequence of genome-wide testing for all women, given the present state of knowledge? What currently is in practice is uncertainty of the meaning of genomewide test results in many instances, an unpredictability concerning the penetrance and expressivity of a wide spectrum of genomic changes at the submicroscopic level, and an accompanying lack of precise genotype–phenotype correlation. What is not in place are the components necessary to assure the integrity of a pregnant woman’s decision-making whether to undergo fetal genome-wide testing. This includes the formal education of practitioners and counselors concerning the science of interpretation of genomic information as well as established approaches dealing with uncertainty; the composition of healthcare providers interpreting genome-wide testing results to a pregnant woman; uniform and standardized guidelines by professional and governmental organizations; detailed knowledge of pregnant women’s attitudes and desires; and, complete understanding and knowledge of genotype–phenotype correlations based on in utero (as opposed to postnatal) expression. The wide variable expression associated with 22q11.2, both physically and intellectually, dramatizes the counseling dilemma generated by genome-wide testing of all women. When intelligence scores in this instance range from a low of 60 to a high approaching 100, it has yet to be specifically established what and how this information is to be communicated. It would appear that this circumstance is reminiscent of a time when no prenatal genetic testing was available and pregnant women could only be given odds. When women experience abnormal genomic results, these are their responses: “an offer too good to pass up,” “blindsided by the results,” “uncertainty and unquantifiable risks,” “need for support,” and, most telling, “toxic knowledge ”.13
CONCLUSIONS (BASED ON THE PRESENTATIONS AND THE DISCUSSION PERIOD WITH THE PRESENTERS AND THE AUDIENCE) 1. The audience consensus, polled prior to the debate by a “show of hands” indicated a 60–65% support for the recommendation of genome-wide testing when there is prenatal identification of congenital anomalies by the screening ultrasound test.
2. Following the debate and discussion, the audience consensus had reversed their support for the recommendation as there was a great amount of discussion related to: 2.1 The present but variable process for patient education and genetic understanding of the genomic technology; 2.2 The requirement that “true” maternal informed consent was required considering the benefits and risks of the fetal genomic information and the recognition that the prenatal diagnosis technique (chorionic villus sampling (CVS);
21
amniocentesis (A)) required to undertake the genomic fetal testing had a risk of pregnancy loss estimated at 0.5–1.0%; 2.3 The audience’s opinion indicated that the genetic counseling/ knowledge translation systems varied internationally and that if the recommendation was to be implemented, a welldesigned system of informed consent with pre and post testing support was required along with well-defined laboratory and genetic reporting standards. The counseling time and the genetic human resource implications for this recommendation and the implementation process were discussed. 2.4 The discussion between presenters and the audience, related to specific mutations with childhood cognitive morbidity, was interactive and passionately argued by supporters and non-supporters of the recommendation. 2.5 The option for prenatal or postnatal therapy directed at improved childhood outcomes is a compelling argument, but this aspect will require more investigation and follow-up. 3. The final consensus summary is that, while the present genomic diagnostic technology with access to prenatal testing following an informed consent process recommendation would likely become a “future” standard of care for prenatal screening/diagnosis/therapy when specific fetal anomalies/syndromes are identified, the debate recommendation could not be completely supported, at this time, by the international audience attending the 2014 18th ISPD meeting in Brisbane Australia.
ACKNOWLEDGEMENTS The co-author (EP) wishes to acknowledge that his presented and written opinion is based, in part, on the Ph.D Thesis of Eline Bunnick of Rotterdam Erasmus University, Netherlands, “Up close and personal: ethical issues in genetic testing.” 2013 as summarized by Peter Schielen, Ph.D., in Prenatal Perspectives, Volume 2, Number 2, 2014.
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • Congenital anomalies are common in human reproduction and have a prevalence of 5%. • Molecular fetal karyotyping using microarray analysis will detect more pathogenic chromosomal anomalies. • Patient understanding related to the complexity and the information identified with fetal microarray testing is variable and very limited.
WHAT DOES THIS STUDY ADD? • More consistent and in-depth patient counseling is required so that this new technology can be used for higher levels of informed consent, for better diagnostic information, and within an appropriate ethical framework.
REFERENCES 1. Jones KL, Jones MC, del Campo M. Smith’s Recognizable Patterns of Human Malformation (7th edn). Saunders Elsevier: Philadelphia, 2013;1–6. 2. Firth HV, Hurst JA. Oxford Desk Reference Clinical Genetics. Oxford University Press: Oxford, 2005;4–5. 3. Bunnik EM, De Jong A, Nijsingh N, De Wert GMWR. The New Genetics and Informed Consent: Differentiating Choice to Preservers Autonomy. Bioethics 2013;27(6):348–55. 4. McGillivray G, Rosenfeld JA, McKinlay Gardner M, Gillam LH. Genetic counselling and ethical issues with chromosome microarray analysis in prenatal testing. Prenat Diagn 2012;32:389–95.
Prenatal Diagnosis 2015, 35, 19–22
5. Donnelly JC, Platt LD, Rebarber A, et al. Association of Copy Number variants with Specific Ultrasonographically Detected Fetal Anomalies. Obstet Gynecol 2014;124:83–90. 6. Miller DT. Consensus statement on chromosomal microarray as a firsttier clinical diagnostic test for individuals with developmental delay/ intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. Am J Hum Genet 2010;86:749–64. 7. Manning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 2010;12:742–5.
© 2014 John Wiley & Sons, Ltd.
22
8. Wapner, RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012;367:2175–84. 9. Ledbetter DH, Riggs ER, Martin CL. Clinical applications of wholegenome chromosomal microarray analysis. In Genomic and Personalized Medicine (2nd edn). Elsevier: Amsterdam, 2013;133–44. 10. Moreno-De-Luca A. Clinical variability in individuals with 16p11.2 deletions is partially explained by parental cognitive, behavioral and motor profiles. Biol Psychiatry 2014; PII: S0006-3223 (14) 00427-2, doi: 10.1016/j.biopsych.2014.04.021.
Prenatal Diagnosis 2015, 35, 19–22
R. D. Wilson et al.
11. Cheung EN, George SR, Andrade DM, et al. Neonatal hypocalcemia, neonatal seizures, and intellectual disability in 22q11.2 deletion syndrome. Genet Med 2014;16:40–4. 12. Samango-Sprouse CA, Sadeghin T, Mitchell FL, et al. Postive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47,XXY syndrome at 36 and 72 months of age. Am J Med Genet A 2013;161:501–8. 13. Bernhardt BA, Soucier D, Hanson K, et al. Women’s experiences receiving abnormal prenatal chromosomal microarray testing results. Genet Med 2013;15(2):139–45.
© 2014 John Wiley & Sons, Ltd.
