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Preimplantation Diagnosis for Single Gene Disorders Victoria K. Berger, MD1

Valerie L. Baker, MD1

1 Department of Obstetrics and Gynecology, Stanford University

School of Medicine, Stanford, California

Address for correspondence Victoria K. Berger, MD, Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 (e-mail: [email protected]).

Abstract

Keywords

► preimplantation genetic diagnosis ► monogenic disorder ► single gene disorder ► embryo biopsy

Preimplantation genetic diagnosis (PGD) allows patients who are carriers or who are affected by genetic diseases to select unaffected embryos for transfer before becoming pregnant. The practice of PGD is evolving with rapid advances in technology and biopsy methods. Testing for a specific gene mutation can be performed in combination with 24-chromosome aneuploidy screening. Several unique applications of PGD are reviewed, including exclusion diagnosis for couples from Huntington disease families, testing for fragile X premutations, and human leukocyte antigen matching for stem cell donor siblings. Although PGD for single gene mutations allows patients to gain information about their embryos and perhaps avoid a difficult decision about whether or not to terminate an ongoing pregnancy, this technique also provides for much ethical debate encompassing the well-being of the prospective couple, embryo, child, and people in the community affected by the diseases being screened.

Utilization Preimplantation genetic diagnosis (PGD) is used as part of in vitro fertilization (IVF) cycles to allow patients at risk for passing on a potentially serious disease to their offspring the option of screening embryos before becoming pregnant. Although there is no way to prevent the creation of an embryo that will be affected by a disorder, testing embryos for specific mutations prevent patients from having to make a difficult decision of testing during pregnancy and potentially proceeding with termination of an affected fetus once the pregnancy is ongoing. In 1990, Handyside et al reported the first established pregnancies, which used PGD for patients carrying mutations for adrenoleukodystrophy and X-linked mental retardation.1 In these cases, sex was determined by DNA amplification of a Y chromosome-specific repeat sequence and female embryos were chosen for transfer. With advances over the past two decades, testing can be performed specifically for single gene disorders, not only for sex. The most recent available data from the Society for Assisted Reproductive Technology (SART) reported that 66.2% of centers performed preimplantation genetic testing (PGT) in 2008 and PGT was used in 4.2% of all fresh nondonor cycles.2 Although the

Issue Theme Selecting the Best Embryo; Guest Editor, Valerie L. Baker, MD

most common indication for PGT was aneuploidy screening in the SART Clinical Outcomes Reporting database, use of PGD for monogenic disorders increased from 2007 to 2008.2 The European Society of Human Reproduction and Embryology (ESHRE) PGD consortium for cycles occurring in 2008 reported that a total of 5,641 PGT cycles were performed in 2008 of which 24% were for single gene disorders.3 Although increasing, the relatively modest use of PGD for single gene mutations may be in part be explained by the fact that patients benefiting from embryo selection often do not have baseline infertility and are not seen at infertility centers.4 In contrast, primary care physicians have the most contact with these patients, but have various levels of comfort regarding counseling and referral. In 2009, Klitzman et al surveyed more than 200 internists in the United States regarding their views toward the utilization of PGD, and found that 7.1% were comfortable counseling about PGD and 4.9% have recommended PGD to patients. Of those who responded to the survey, 34% stated that they would refer to a practice performing PGD for the indication of cystic fibrosis (CF), the most commonly agreed upon indication by this group.4 A survey conducted in 2007 assessing the opinions of gynecologic oncologists and

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DOI http://dx.doi.org/ 10.1055/s-0033-1363552. ISSN 1526-8004.

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Semin Reprod Med 2014;32:107–113

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obstetrician/gynecologists regarding PGD for hereditary cancer syndromes demonstrated that 29% have referred patients to a PGD provider.5 These authors concluded that more medical education is needed to increase primary care physician’s knowledge of PGD practices.

Indications PGD practices vary by geographic locations and the indications for which PGD is performed have largely increased over the years. In Europe, national regulations vary, and PGD is either prohibited, allowed, or practiced in the absence of recommendations, whereas in the United States, government does not regulate its practice.6–8 Of note, the European Court of Human Rights overturned Italy’s ban on PGD of embryos for couples seeking to have a baby through in vitro fertilization (IVF). Prior regulation had allowed termination of pregnancy for an affected fetus, but had not allowed biopsy of embryos. For the majority of the past two decades, CF and spinal muscular atrophy have been the most common autosomal recessive disorders which have been screened by PGD. In the autosomal dominant category, myotonic dystrophy and Huntington disease (HD) have historically been the most requested. ►Table 1 lists the common indications by type of disorder. Importantly, the trend over past 10 years has been noted for a large expansion in what the ESHRE review categorized as “other” indications, with testing performed for more than 150 different disorders in the published review of 2007 to 2008 data.9,10

Procedures The procedures employed for PGD have been rapidly evolving over the past several years with novel technologies to improve utilization and outcomes. Intracytoplasmic sperm in-

Table 1 Indications and examples of commonly tested mutations by type of disorder Autosomal recessive disorders

Cystic fibrosis, spinal muscle atrophy, β-thalassemia

Autosomal dominant disorders

Myotonic dystrophy type I, Huntington disease, spinal cerebellar ataxia (several types)

X-linked disorders

Duchenne muscular dystrophy, hemophilia, fragile X syndrome

Cancer predisposing genes

Neurofibromatosis type 1, familial adenomatous polyposis, BRCA1 and 2

HLA matching

HLA added to β-thalassemia and sickle cell

Mitochondrial disorders

Rare indication

Unknown genes by linkage analysis

Various genetic disorders

Abbreviation: HLA, human leukocyte antigen.

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jection (ICSI) is recommended for single gene PGD to decrease contamination.9,11 Biopsy of the cells for genetic analysis can be performed in three different developmental stages: polar body, cleavage stage, and blastocyst. At the cleavage stage, biopsy is performed, with extraction of one to two cells, followed by fresh transfer of the unaffected embryos.9 However, practice appears to be transitioning to blastocyst biopsy, with cryopreservation of the biopsied blastocysts if results are not available by the next day. This method allows a greater number cells to be analyzed with studies showing reduction of amplification failure and allele dropout.2,12–14 Chang et al examined methods for blastocyst biopsy with vitrification and showed a 94% survival rate of vitrified blastocysts with a 50% implantation rate.12 Cryopreservation of biopsied blastocysts is a useful technique which allows for more diagnostic time, transfer into a more physiologic endometrium, and avoidance of ovarian hyperstimulation in at-risk patients.12,15 It is also possible to biopsy cryopreserved blastocysts, if the need for biopsy is not determined until after the blastocysts are frozen, such as when a couple has a child affected with a disorder from their fresh embryo transfer. Although historically PGD has been performed for single gene mutations only without concurrent analysis for aneuploidy, with advances in technology to perform 24-chromosome aneuploidy screening, single gene PGD can now be combined with aneuploidy screening with promising results.16 Patients carrying a mutation have the option to select unaffected and euploid embryos with potentially increased chance for successful pregnancy. In a recent abstract, Rabinowitz et al reported data on 54 patients undergoing PGD for single gene disorders along with aneuploidy screening, of which 68% transferred unaffected and euploid embryos and all patients had prenatal diagnosis (PND) or testing of live births confirming PGD results.17 A study by Rechitsky et al also recently demonstrated favorable success rates for 24-chromosomes aneuploidy screening along with testing for CF and other genetic conditions.18 A newer application to PGD for monogenic disorders is next-generation sequencing (NGS). Treff et al demonstrated NGS of blastocyst biopsy provides dependable PGD information, suggesting that role of NGS is likely to expand in the future.19,20

Success Rates Patients undergoing PGD for single gene mutations may have improved success rates compared with patients undergoing PGD for aneuploidy, structural chromosome abnormalities, or sex selection, but this is not certain. The ESHRE PGD consortium data analysis of the past 10 years’ experience demonstrated a clinical pregnancy rate of 22% per oocyte retrieval and 29% per embryo transfer.10 The most recent available data from SART reflects practice in 2007 to 2008 when embryo biopsy for single gene disorders was performed on day 3, aneuploidy screening was not done concurrently, and transfer occurred in the fresh cycle. In this time frame, the reported delivery rate was 31.6% per oocyte retrieval if PGD was performed, with no data available regarding cycles in which PGD was intended but then not performed.2 These relatively

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favorable pregnancy rates may be explained by the younger age of women undergoing PGD for monogenic mutations as compared with those undergoing PGD for aneuploidy screening.2 The SART data also noted fewer cancellation cycles in the single gene indication group, conceivably in part owing to 50% of embryos being suitable for transfer in autosomal dominant conditions where one parent is affected and 75% of embryos remaining disease free in the autosomal recessive conditions where both parents are carriers, in addition to the fact that aneuploidy screening was not typically being performed concurrently during that time frame.2 However, how likely a couple is to be successful may also be affected by the disease for which they are using PGD, as there may be an inherently poorer response to IVF for some disorders, most notably fragile X mental retardation-1 (FMR1) premutation carriers who may have low ovarian reserve.21 As noted above, it is important to emphasize the limitations of the current data when interpreting success rates of PGD. Clinical pregnancy and live birth rates are described per oocyte retrieval or embryo transfer. This means that the denominator used to calculate live birth rates does not include patients whose cycles were cancelled due to either poor ovarian response or poor embryo quality and therefore did not proceed with biopsy, or in some cases retrieval or transfer. It will prove beneficial to examine success per intended PGD cycle start as this may provide more accurate representation of success rates. In addition, the success data are lagging as the newest figures from ESHRE include cycles from 2008 to 2009, the majority of which uses cleavage stage biopsy. In fact, arguments have been made that the success rates seen may be higher with trophectoderm biopsy in relatively young healthy women because of the detrimental effect of blastomere biopsy, which has been associated with a reduction in implantation rate.13,22 However, it should be noted that trophectoderm biopsy for single gene disorders may necessitate freezing all embryos. Although misdiagnosis is thought to be a rare event, the misdiagnosis rate can be difficult to determine.10 Misdiagnosis events may not be reported by some centers or be may be missed as many embryos do not result in ongoing pregnancies. The update of ESHRE PGD reported an adverse misdiagnosis rate of 0.27%, with most errors occurring in early PGD years.10,23

Special Considerations Adult Onset Disorders Although PGD was originally used to reduce the risk of inheritance of disorders with onset in childhood, over the past 20 years, it has been increasingly applied for adult onset diseases. Several ethical dilemmas accompany the use of PGD in this setting as certain genes have variable penetrance and genetically affected people may never show phenotypic expression of the disease.24 Proponents argue that prospective parents should be able to negate the risk of their future children developing a serious condition in adulthood since the anticipation may cause significant psychological distress.25 Both the American Society for Reproductive Medicine

Berger, Baker

ethics committee for adult onset conditions and the ESHRE ethics task force concluded that late onset disorders are appropriate indications for PGD.25,26 HD, an autosomal dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat,27,28 is currently one of the most common indications in this category of adult onset disease.10 In general, the size of the CAG expansion is inversely correlated with the age of onset of symptoms. The repeat size may be unstable and can expand.29 HD presents in the third to fifth decade and patients from HD families may not be aware of their carrier status when considering childbearing. Couples who want to know their genetic risk can undergo presymptomatic testing and choose PGD or testing and termination of an affected fetus during the pregnancy if they are carriers of the expanded allele but do not wish to pass the mutation to their offspring.30 In addition, options exist for patients at 50% risk of being an HD carrier, who do not want to know their carrier status but desire genetically related children. Linked marker analysis without direct testing of the repeat is used in exclusion testing. The transmission of the HD region from the affected grandparent is followed. If one of the two alleles from the affected grandparent is found, the embryo (in the case of PGD) or fetus (in the case of testing during pregnancy) has a 50% risk of being a carrier.30–32 In PGD, embryos at 50% risk would not be transferred, whereas in PND, a couple carrying a fetus determined to have 50% risk of being a carrier may face a decision of whether or not to terminate the pregnancy. In addition, it is possible for a couple to undergo nondisclosure PGD with direct testing for the expanded allele, but the couple never be told the results of the testing (i.e., whether or not any of the embryos carried HD). In this scenario, the couple is instead only told that the embryos being transferred are not affected. Embryos may not be transferrable due to being HD carrier, aneuploid, or of poor quality, so the patient will never know his or her carrier status even if there is no transferrable embryo. Patients may choose to not even know the number of developing follicles, number of oocytes retrieved, and number of embryos created to avoid having suspicion of being an HD carrier status if there are a high number of embryos created but no transferrable embryo. A recently published study evaluating utilization of PGD and prenatal diagnosis (PND) by HD carriers and at-risk patients in The Netherlands between 1998 and 2008 demonstrated that in this time frame, a minority of patients opted for PGD as compared with PND.30 However, as the authors point out, this trend may be influenced by illegality of exclusion PND in The Netherlands, requiring referral to other countries and there may have been changes in utilization of PGD over the past few years.30 The authors also noted that delivery rates of unaffected children are overall superior in patients undergoing PND as compared with PGD; however, these improved outcomes are at the price of some PND couples electing termination of pregnancy, of which psychological stress must not be undervalued.30

Cancer Predisposing Genes Cancer predisposing genes are becoming more acknowledged as indicators for PGD. Studies have reported successful Seminars in Reproductive Medicine

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outcomes with genes responsible for Lynch syndrome, multiple endocrine neoplasia, neurofibromatosis type 2, Von Hippel Lindau syndrome, and many others.33–37 Patients who are carriers of the BRCA1 and BRCA2 genes comprise a unique group possibly benefiting from PGD. The theoretical increase risk of ovulation induction in these patients who are prone to breast and ovarian cancer has appropriately led to cautionary practice of PGD.38 A small study by Sagi et al demonstrated successful pregnancies in BRCA carriers with baseline infertility.39 The authors noted that couples who require IVF will understandably be more willing to accept risks of ovulation induction in these circumstances.39 A study evaluating the opinions of BRCA mutation carriers regarding reproductive genetic testing showed that ovulation induction is a strong deterrent for many people. However, participants felt that terminating an affected pregnancy is not justifiable in the case of hereditary cancer mutations and considered PGD a more acceptable route.40

Fragile X Syndrome Fragile X syndrome is the most common inherited cause of intellectual disability. Male phenotype is usually severe with dysmorphic features and cognitive disability while females may present with milder manifestations. A trinucleotide CGG expansion in the FMR1 gene is the etiology of the syndrome with a fully expanded mutation, > 200 CGG repeats, resulting in an affected phenotype in a male and variable expression in female due to X-inactivation. Women who carry a premutation of fragile X, 55 to 200 CGG repeats, are at risk of having affected children as the premutation repeats are unstable and may expand into a full mutation.21,41 Testing for fragile X may be performed during pregnancy42,43 or before conception.43 If a woman is known to be a carrier of a fragile X premutation, PGD may be considered. Several obstacles are encountered in PGD for fragile X syndrome, including decrease in ovarian function for some patients and technical difficulties in molecular diagnosis. Primary ovarian insufficiency is seen in 10 to 26% of women with fragile X premutations.41,44 Patients carrying a fragile X premutation may have a higher gonadotropin requirement with significantly fewer oocytes retrieved. However, if an appropriate ovarian response is established, embryo quality, embryo transfer, and pregnancy rates are similar to PGD cycles for other indications.21 Bibi et al examined the relationship between CGG repeat number and ovarian response in fragile X premutation PGD cycles, showing improved outcomes in patients with > 100 CGG repeats. The authors concluded that patients with < 100 CCG repeats should be managed as poor responders, even in the setting of normal FSH levels.45 The technical difficulties are inherent to the mutation itself, as long repeats may not be amplified accurately with polymerase chain reaction methods. Diagnosis can be based on identifying two normal alleles in an embryo before deciding an embryo is suitable for transfer.21,46 It is possible to screen embryos for the copy of the X chromosome that contains the premutation, particularly if DNA samples are available from an additional generation (parents or other children), but it is not possible to quantify the exact repeat Seminars in Reproductive Medicine

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number seen in each embryo to determine whether the premutation expanded or contracted in the embryo. It is also not fully understood when in development fragile X premutations expand; so transfer of an embryo which carries a premutation allele that appears to not have expanded to the full mutation would not necessarily prevent a pregnancy with a fetus with > 200 CGG repeats and fragile X syndrome.

Human Leukocyte Antigen Matching Sibling PGD with human leukocyte antigen (HLA) typing allows parents to select an embryo with a potential to become a hemapoietic stem cell donor to an affected sibling. The first description of PGD with HLA typing was published by Verlinsky et al47 in 2001. Parents who have a child affected by a hereditary disease such as β-thalassemia or sickle cell anemia which may cured by stem cell transplant can now use PGD with HLA typing to select a nonaffected and HLA-matched embryo.10,48 However, couples who have a child affected by a disease, such as leukemia which may be cured hemapoietic stem cell transplantation from an HLA-matched donor, may undergo PGD cycles with HLA as primary purpose.49 In both situations, the goal is to conceive a healthy offspring that can save an already gravely sick child, the so-called “savior” sibling.50 Kahraman et al recently reported, in one of the largest studies to date, birth of 59 healthy and HLA-matched children with 21 siblings cured from their respective diseases by hemapoietic stem cell transplant.51 Several difficulties are inherent in the process of PGD with HLA typing. Although theoretically there is a 25% chance of HLA matching, when combining selection against a mutation with HLA typing and aneuploidy screening, the percentage of embryos left to transfer is low. In the study of Kahraman et al, 12.5% of embryos were transferrable with a 34.9% clinical pregnancy rate per embryo transfer.51 An earlier study from two European centers reported a 15.9% live birth rate per cycle start.52 If a woman is a poor responder, the intended parents may be left with no embryo available for transfer. Some patients face the dilemma of choosing to transfer a poor quality embryo or one that is unaffected but not an HLA match. Once a clinical pregnancy is achieved, a risk of miscarriage still remains. Although psychologically demanding process, many couples will ultimately continue trying as conceivably possible to produce a donor sibling to save their sick child.53 HLA typing to create a “savior” sibling has been the topic of a difficult ethical debate. The ESHRE PGD consortium guidelines from 2011 state that HLA typing is acceptable if affected child has a good chance of being cured from disease.54 Critics argue that the intention of producing an HLA-matched embryo encompasses the notion that potentially healthy embryos will be discarded and question the moral obligations toward the embryo.50 Others suggest that saving the life of a sick child may in fact be a morally justified reason to undergo a process through which embryos may be discarded.50 Another criticism is that parents are bringing a child into the world that they may otherwise not desired if they did not have an already sick child in need of cure. However, it has been noted that the vast majority of the

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Requirement of IVF/ICSI

Requires patients with no baseline infertility to undergo IVF/ICSI High cost, potentially low efficiency Increase risk of multiples and prematurity if more than one embryo is selected for transfer

Embryos

May require embryos to be discarded or donated to research, transfer of poor quality embryos over better quality embryos affected with disorder

Effects on couples

Psychologically and physically straining May face disapproval from affected family members

Effects on future children

No evidence of harm, but long-term data lacking Psychological effects on “savior” siblings later in life unknown

Effects on affected

Some consider practice to devalue the lives of those individuals affected Some prefer for others not to suffer like they have

Responsibility of physician vs. patient

Autonomy of patient to choose the most suited embryo Physician’s role if patients decide to transfer an affected embryo

Research

Ability to create cell lines with disease mutation for study

Abbreviations: ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization.

couples in these situations genuinely want a healthy child and potentially have even chosen to delay conceiving to take care of their sick child.55 Questions over welfare and psychological impact of the child being brought into the world to save a sibling’s life are appropriately raised and most are in agreement that this process should be done with multidisciplinary approach to ensure the psychological well-being of all involved.53,55 The potential financial cost and burden on a family should not be underestimated, especially as this process may prove to be expensive and inefficient in some circumstances.50,51,53

Cost-Effectiveness The cost of IVF and PGD is high, and some patients undergoing PGD for single gene disorders do not have baseline infertility necessitating reproductive assistance. However, the financial burden of lifetime illness is also quiet substantial and some have proposed PGD as a means of decreasing societal costs. For example, CF, a prevalent autosomal recessive disease, characterized by respiratory and gastrointestinal symptoms due to a defective chloride channel causing thick mucus secretion, is a progressive disease with a current life expectancy of late 30s.56,57 American Congress of Obstetricians and Gynecologists recommends offering prenatal screening for CF as routine care in women of reproductive age.58 Given relatively high genetic carrier prevalence in the population and significant expense of caring for an affected child, it has been suggested that couples be offered the option of IVF and PGD. One cost-benefit analysis demonstrated a benefit in PGD over natural conception in women up to the age of 40.59 A second cost-benefit analysis comparing the cost of PGD and transfer of unaffected embryos with the cost of raising affecting children also found high net savings with PGD.60

Ethical Considerations Although PGD provides couples who carry a serious genetic disease an opportunity to bring a healthy child into the world,

its practice has been the center of many moral and ethical reflections. ►Table 2 provides an overview of the various ethical considerations. One of the more difficult debates by critics and family members of affected individuals has been the argument that selecting embryos without mutations diminishes the importance of people disabled by the diseases.25,61,62 However, for most couples, the choice to proceed with PGD is not driven by these notions. Several studies have demonstrated that the decision to proceed with PGD is quite complex, encompassing many considerations,63 with the consensus that most proceed with PGD to protect their future children against the suffering they witness in other family members.30,31,40,62 Critics have also warned against PGD practice moving toward a “designer child,” likely stemming from ability to use PGD for variable penetrance and cancer predisposing genes and particularly with the prospect of comprehensive embryo testing.34,38,64 Ethical obligations of the physician have been examined with concerns about providing a plethora of complicated genetic information to patients and about the uncertainty regarding on whom the responsibility befalls to select the optimal embryo.65 If a poor responder couple decides to transfer an affected embryo, the role of the physician in relation to patient autonomy becomes more complex. The nature of the mutation also plays a role, given that a severe disease poses different risks as compared with a cancer predisposing gene with variable penetrance. Other opponents comment on the uncertainty of the effects and possible consequences of a biopsy of an embryo in one of earliest stages of development on the future child.61 To date, studies have not shown any negative impact of PGD on children and quoted fetal malformations and adverse outcome rates similar to that of babies born with IVF/ICSI.10,26,66 A recent study by Thomaidis et al67 evaluated cognitive and motor development of PGD children ages 2 to 7, reporting that a majority of participants demonstrated normal skills and half of the children with developmental delay were born prematurely.67 Although outcomes presented are reassuring, long-term data are limited and further follow-up investigation is warranted. Seminars in Reproductive Medicine

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Table 2 Ethical considerations in preimplantation genetic diagnosis for single gene disorders

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Berger, Baker 15 Lathi RB, Massie JA, Gilani M, et al. Outcomes of trophectoderm

Conclusions PGD provides patients who are carriers of genetic mutations and opportunity to select unaffected embryos for transfer. Embryos may be screened for the genetic mutation along with 24-chromosome aneuploidy screening or HLA matching. Although PGD is diagnostically accurate with overall reassuring pregnancy and live birth rates, its utilization is subject to many important ethical debates concerning all involved parties. The practice of PGD for single gene disorders is evolving very rapidly, and continued surveillance of clinical outcomes is mandatory for ensuring optimal patient care.

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Seminars in Reproductive Medicine

Vol. 32

No. 2/2014

113

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Preimplantation Diagnosis for Single Gene Disorders

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