Preimplantation Genetic Diagnosis

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Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.

Introduction

Human Embryo (day 3)
Human Embryo (day 5)

This current page is a general starting point for the topic of Preimplantation Genetic Screening also called Preimplantation Genetic Diagnosis. Recently with the growth in Assisted Reproductive Technology (ART) or commonly known as In Vitro Fertilization (IVF), there is now a new form of prenatal diagnosis that involves genetic testing of the blastocyst before implantation. (More? Assisted Reproductive Technology)

Generally, in vitro fertilised embryos are first cultured for up to three days. By this time the conceptus is composed of 6 to 10 cells (blastomeres) from which 1 or 2 cells are then removed by a laser for genetic testing. Some studies have also removed cells, or the polar body, at earlier days following fertilisation. While other studies have collected cells from later stage (day 5) blastocyst either the trophectoderm (trophoblast) or inner cell mass (embryoblast).


This Embryology site is a developmental educational resource, it does not provide specific clinical details, you should always refer to a health professional.


Diagnosis Links: Prenatal Diagnosis | Pregnancy Test | Amniocentesis | Chorionic villus sampling | Ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Non-Invasive Prenatal Testing | Fetal Cells in Maternal Blood | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Genome Sequencing | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Classification of Diseases | Category:Neonatal Diagnosis
| Assisted Reproductive Technology | In Vitro Fertilization

Some Recent Findings

  • Review - Genetic Analysis of Human Preimplantation Embryos[1] "Preimplantation development comprises the initial stages of mammalian development, before the embryo implants into the mother's uterus. In normal conditions, after fertilization the embryo grows until reaching blastocyst stage. The blastocyst grows as the cells divide and the cavity expands, until it arrives at the uterus, where it "hatches" from the zona pellucida to implant into the uterine wall. Nevertheless, embryo quality and viability can be affected by chromosomal abnormalities, most of which occur during gametogenesis and early embryo development; human embryos produced in vitro are especially vulnerable. Therefore, the selection of chromosomally normal embryos for transfer in assisted reproduction can improve outcomes in poor-prognosis patients. Additionally, in couples with an inherited disorder, early diagnosis could prevent pregnancy with an affected child and would, thereby, avoid the therapeutic interruption of pregnancy. These concerns have prompted advancements in the use of preimplantation genetic diagnosis (PGD). Genetic testing is applied in two different scenarios: in couples with an inherited genetic disorder or carriers of a structural chromosomal abnormality, it is termed PGD; in infertile couples with increased risk of generating embryos with de novo chromosome abnormalities, it is termed preimplantation genetic screening, or PGS."
  • Preimplantation genetic screening (PGS) still in search of a clinical application: a systematic review[2] "Only a few years ago the American Society of Assisted Reproductive Medicine (ASRM), the European Society for Human Reproduction and Embryology (ESHRE) and the British Fertility Society declared preimplantation genetic screening (PGS#1) ineffective in improving in vitro fertilization (IVF) pregnancy rates and in reducing miscarriage rates. A presumably upgraded form of the procedure (PGS#2) has recently been reintroduced, and is here assessed in a systematic review. PGS#2 in comparison to PGS#1 is characterized by: (i) trophectoderm biopsy on day 5/6 embryos in place of day-3 embryo biopsy; and (ii) fluorescence in-situ hybridization (FISH) of limited chromosome numbers is replaced by techniques, allowing aneuploidy assessments of all 24 chromosome pairs. Reviewing the literature, we were unable to identify properly conducted prospective clinical trials in which IVF outcomes were assessed based on "intent to treat"."
  • Origins and rates of aneuploidy in human blastomeres[3] "The rate of maternal meiotic trisomy rose significantly with age, whereas other types of trisomy showed no correlation with age. Trisomies were mostly maternal in origin, whereas paternal and maternal monosomies were roughly equal in frequency. No examples of paternal meiotic trisomy were observed. Segmental error rates were found to be independent of maternal age."
  • Preimplantation genetic diagnosis for inherited breast cancer: first clinical application and live birth in Spain[4] "Carriers of a mutation in BRCA1/2 genes confront a high lifetime risk of breast and ovarian cancer and fifty percent probability of passing the mutation to their offspring. ...A 28-year-old BRCA1 mutation carrier (5273G>A in exon 19) with a strong maternal history of breast cancer and 2 years of infertility decided to pursue PGD to have a healthy descendent after an accurate assessment of her reproductive options. The procedure was approved by the national regulation authority and a PGD cycle was initiated. Four out of 6 embryos harbored the mutation. The two unaffected embryos were implanted in the uterus. A singleton pregnancy was achieved and a male baby was delivered at term. Consented umbilical cord blood testing confirmed the accuracy of the technique. Individualized PGD for inherited breast predisposition is feasible in the context of a multidisciplinary team."
  • Preimplantation genetic diagnosis (PGD) for Huntington's disease: the experience of three European centres[5] "This study provides an overview of 13 years of experience of preimplantation genetic diagnosis (PGD) for Huntington's disease (HD) at three European PGD centres in Brussels, Maastricht and Strasbourg. ... PGD workup was based on two approaches: (1) direct testing of the CAG-triplet repeat and (2) linkage analysis using intragenic or flanking microsatellite markers of the HTT gene. In total, 257 couples had started workup and 174 couples (70% direct testing, 30% exclusion testing) completed at least one PGD cycle. In total, 389 cycles continued to oocyte retrieval (OR). The delivery rates per OR were 19.8%, and per embryo transfer 24.8%, resulting in 77 deliveries and the birth of 90 children. We conclude that PGD is a valuable and safe reproductive option for HD carriers and couples at risk of transmitting HD."

Genetic Testing

Trisomy

Trisomy 21 karyotype cartoon

There are clinically more and more tests becoming available as we learn more about the genetic basis of some diseases. The most common diagnostic test relates to the current trend in an increasing maternal age, which has long been associated with an increase in genetic abnormalities, the most frequent of these is trisomy 21 or Down syndrome.

Links: Genetic risk maternal age | Trisomy 21

Single Gene Disorders

  • Cystic fibrosis
  • beta-thalassaemia
  • Spinal muscular atrophy
  • Sickle-cell anaemia
  • Huntington disease
  • Myotonic dystrophy type 1
  • Duchenne or Becker muscular dystrophy
  • Haemophilia
  • Fragile-X syndrome

Australia

A recent publication from NHMRC Medical Genetic Testing: information for health professionals (2010). This paper covers background information on all types of genetic tests, not just those associated with prenatal diagnosis.

Types of genetic tests

  • Somatic cell genetic testing involves testing tissue (usually cancer) for non-heritable mutations. This may be for diagnostic purposes, or to assist in selecting treatment for a known cancer.
  • Diagnostic testing for heritable mutations involves testing an affected person to identify the underlying mutation(s) responsible for the disease. This typically involves testing one or more genes for a heritable mutation.
  • Predictive testing for heritable mutations involves testing an unaffected person for a germline mutation identified in genetic relatives. The risk of disease will vary according to the gene, the mutation and the family history.
  • Carrier testing for heritable mutations involves testing for the presence of a mutation that does not place the person at increased risk of developing the disease, but does increase the risk of having an affected child developing the disease.
  • Pharmacogenetic testing for a genetic variant that alters the way a drug is metabolised. These variants can involve somatic cells or germline changes. Even if these variants are heritable (that is germline changes), the tests are usually of relevance to genetic relatives only if they are being treated with the same type of medication.


Links: NHMRC - Medical Genetic Testing: information for health professionals

USA

A new site developed by NIH "GeneTests" provides medical genetics information resources available at no cost to all interested persons. It contains educational information, a directory of genetic testing laboratories and links to other databases such as OMIM.


Links: GeneTests | Medline Plus - Genetic Testing

Ethics of Testing

Major developmental abnormalities detected early enough can be resolved far more easily than those discovered late in a pregnancy.

What are the ethical questions that are raised by prenatal testing? Future individual rights or parents rights? But what about diseases, like Huntington's, where a diagnostic test can be made but there are no current treatments for the postnatal (95% of cases adult onset) disease?

Huntington's disease

Guidelines for the molecular genetics predictive test

Recommendation 2.1 "the test is available only to individuals who have reached the age of majority."
Recommendation 7.2 "the couple requesting antenatal testing must be clearly informed that if they intend to complete the pregnancy if the fetus is a carrier of the gene defect, there is no valid reason for performing the test."

(excerpt from: IHA and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease.)

References

  1. S Garcia-Herrero, A Cervero, E Mateu, P Mir, M E Póo, L Rodrigo, M Vera, C Rubio Genetic Analysis of Human Preimplantation Embryos. Curr. Top. Dev. Biol.: 2016, 120;421-447 PubMed 27475859
  2. Norbert Gleicher, Vitaly A Kushnir, David H Barad Preimplantation genetic screening (PGS) still in search of a clinical application: a systematic review. Reprod. Biol. Endocrinol.: 2014, 12;22 PubMed 24628895
  3. Matthew Rabinowitz, Allison Ryan, George Gemelos, Matthew Hill, Johan Baner, Cengiz Cinnioglu, Milena Banjevic, Dan Potter, Dmitri A Petrov, Zachary Demko Origins and rates of aneuploidy in human blastomeres. Fertil. Steril.: 2012, 97(2);395-401 PubMed 22195772
  4. Teresa Ramón Y Cajal, Ana Polo, Olga Martínez, Carles Giménez, César Arjona, Gemma Llort, Lluís Bassas, Pere Viscasillas, Joaquin Calaf Preimplantation genetic diagnosis for inherited breast cancer: first clinical application and live birth in Spain. Fam. Cancer: 2012, 11(2);175-9 PubMed 22179695
  5. Maartje C Van Rij, Marjan De Rademaeker, Céline Moutou, Jos C F M Dreesen, Martine De Rycke, Inge Liebaers, Joep P M Geraedts, Christine E M De Die-Smulders, Stéphane Viville, BruMaStra PGD working group Preimplantation genetic diagnosis (PGD) for Huntington's disease: the experience of three European centres. Eur. J. Hum. Genet.: 2012, 20(4);368-75 PubMed 22071896

Reviews

Joann Bodurtha, Jerome F Strauss Genomics and perinatal care. N. Engl. J. Med.: 2012, 366(1);64-73 PubMed 22216843

Kim Dao Ly, Ashok Agarwal, Zsolt Peter Nagy Preimplantation genetic screening: does it help or hinder IVF treatment and what is the role of the embryo? J. Assist. Reprod. Genet.: 2011, 28(9);833-49 PubMed 21743973


Articles

Anastasia A Theodosiou, Martin H Johnson The politics of human embryo research and the motivation to achieve PGD. Reprod. Biomed. Online: 2011; PubMed 21397558

G L Harton, M De Rycke, F Fiorentino, C Moutou, S SenGupta, J Traeger-Synodinos, J C Harper, European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium ESHRE PGD consortium best practice guidelines for amplification-based PGD. Hum. Reprod.: 2011, 26(1);33-40 PubMed 20966462

G L Harton, J C Harper, E Coonen, T Pehlivan, K Vesela, L Wilton, European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium ESHRE PGD consortium best practice guidelines for fluorescence in situ hybridization-based PGD. Hum. Reprod.: 2011, 26(1);25-32 PubMed 20966461

G Harton, P Braude, A Lashwood, A Schmutzler, J Traeger-Synodinos, L Wilton, J C Harper, European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium ESHRE PGD consortium best practice guidelines for organization of a PGD centre for PGD/preimplantation genetic screening. Hum. Reprod.: 2011, 26(1);14-24 PubMed 20966460

G L Harton, M C Magli, K Lundin, M Montag, J Lemmen, J C Harper, European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium/Embryology Special Interest Group ESHRE PGD Consortium/Embryology Special Interest Group--best practice guidelines for polar body and embryo biopsy for preimplantation genetic diagnosis/screening (PGD/PGS). Hum. Reprod.: 2011, 26(1);41-6 PubMed 20966459


Journals

Search PubMed

Search Pubmed: Preimplantation Genetic Screening | Preimplantation Genetic Diagnosis



Prenatal Diagnosis Terms

  • ART - Assisted Reproductive Technology a general term to describe all the clinical techniques used to aid fertility.
  • blastomere biopsy - An ART preimplantation genetic diagnosis technique carried out at cleavage stage (day 3), excluding poor quality embryos, detects chromosomal abnormalities of both maternal and paternal origin. May not detect cellular mosaicism in the embryo.
  • blastocyst biopsy - An ART preimplantation genetic diagnosis technique carried out at blastocyst stage (day 4-5), removes several trophoblast (trophoderm) cells, detects chromosomal abnormalities of both maternal and paternal origin and may detect cellular mosaicism.
  • cell-free fetal deoxyribonucleic acid - (cffDNA) refers to fetal DNA circulating and isolated from the plasma portion of maternal blood.
  • false negative rate - The proportion of pregnancies that will test negative given that the congenital anomaly is present.
  • false positive rate - The proportion of pregnancies that will test positive given that the congenital anomaly is absent.
  • negative predictive value - The probability that a congenital anomaly is absent given that the prenatal screening test is negative.
  • Non-Invasive Prenatal Testing - (NIPT) could refer to ultrasound or other imaging techniques, but more frequently used to describe analysis of cell-free fetal DNA circulating in maternal blood.
  • polar body biopsy - (PB biopsy) An ART preimplantation genetic diagnosis technique that removes either the first or second polar body from the zygote. As these are generated by oocyte meiosis they detects chromosomal abnormalities only on the female genetics.
  • positive predictive value - The probability that a congenital anomaly is present given that the prenatal screening test is positive.
  • pre-implantation genetic diagnosis - (PGD, pre-implantation genetic screening) a diagnostic procedure for embryos produced through Assisted Reproductive Technology (ART, in vitro fertilisation, IVF) for genetic diseases that would generate developmental abnormalities or serious postnatal diseases.
  • prenatal screening sensitivity - (detection rate) The probability of testing positive on a prenatal screening test if the congenital anomaly is present.
  • prenatal screening specificity - The probability of testing negative on a prenatal screening test if the congenital anomaly is absent.
  • single nucleotide polymorphisms - (SNPs) the variation in a single DNA nucleotide that occurs at a specific position in the genome.
Other Terms Lists  
Terms Lists: ART | Birth | Bone | Cardiovascular | Gastrointestinal | Genetic | Hearing | Heart | Immune | Integumentary | Neural | Oocyte | Palate | Placenta | Renal | Spermatozoa | Ultrasound | Vision | Historic | Glossary

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Cite this page: Hill, M.A. 2017 Embryology Preimplantation Genetic Diagnosis. Retrieved February 28, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Preimplantation_Genetic_Diagnosis

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© Dr Mark Hill 2017, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G