With fewer embryos now being replaced in each transfer cycle of IVF, embryo selection has become more important than ever. Studies have shown that as many as 50% of embryos are chromosomally abnormal and if transferred such embryos are likely to fail to implant in the uterus or may result in a miscarriage. Embryos have traditionally been chosen according to their appearance under the microscope after 3 or 5 days of development in the incubator. High-tech methods now allow us to perform embryo screening for genetic and chromosomal information.
New techniques of embryo analysis can indicate the chromosomal status of each embryo. This allows us to select high grade embryos for transfer thus reducing the risk of pregnancy failure and improving the chances of having a healthy baby. These advanced techniques of genetic analysis make it possible to screen eggs and embryos for specific abnormalities. The most common embryo testing techniques are preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS).
What is Preimplantation Genetic Diagnosis (PGD)?
PGD is a screening process that enables us to test the embryos of a couple who carry a known genetic marker for a specific inherited disorder so that only healthy embryos are selected to be replaced/transferred to the woman’s uterus in order to attempt to achieve a pregnancy.
PGD testing has been a common practice for more than 20 years and is very successful in detecting genetic alterations in the embryos of couples known to be at risk of passing on an inherited disease to their children. Amongst infertile couples, PGD testing enables the identification of chromosomally normal embryos for transfer which improves IVF pregnancy rates. PGD is of great benefit to women with a history of miscarriage, failed IVF cycles and in those of an older maternal age.
Previously, couples carrying the risk for transmitting genetic disorders were only able to diagnose the health of their unborn child after conception had occurred by amniocentesis. Subsequently, if the pregnancy is affected with the abnormality, couples are faced with the dilemma of having to decide whether they would terminate or continue with the pregnancy. For couples who carry the known risk for a serious inherited disorder, PGD offers an alternative to prenatal testing and pregnancy termination by screening embryos (fertilised eggs) before pregnancy is established.
PGD is performed using a high-powered microscope. One or more cells are removed from the embryo and tested for the genetic trait of interest. The unaffected embryos are identified, separated from the affected embryos, and transferred into the uterus.
What is Preimplantation Genetic Screening (PGS).
PGS generally refers to the screening of chromosomes for aneuploidy (an abnormal number of chromosomes). PGS is the term used more often by fertility specialists when discussing infertility with couples struggling with issues involving age, repeated IVF failures, recurring miscarriages, or having had pregnancies that were genetically abnormal. At Medfem we use PGS to refer to the detection of chromosomally abnormal embryos. This avoids having abnormal embryos transferred to the womb during IVF.
The most commonly known technique for PGS is Array comparative genomic hybridization (aCGH), which analyses a cell from the developing embryo for the correct number of chromosomes. This test can be useful as a screening method for chromosome syndromes and other chromosomal structural changes such as translocations.
What is the difference between PGD and PGS?
PGD involves detection of single gene disorders and PGS involves the detection of chromosomally abnormal embryos that result in IVF failure, miscarriages or babies born with Down’s syndrome (Trisomy 21) or Edward’s Syndrome (Trisomy 18).
Who is PGD for?
PGD is used for individuals who carry one of several hundred known single gene or chromosomal disorders. To name a few:
- Cystic fibrosis
- Huntington’s Disease
- Hypertrophic Cardiomyopathy
- Marfan’s Disease
- Muscular Dystrophy
- Robertsonian Translocations
- Sickle Cell Anemia
- Spinal Muscular Atrophy
- Tay Sachs
Who can benefit from PGD and PGS?
Any couple at risk for passing on a genetic disease or condition can benefit from pre-implantation genetic diagnosis and screening. Possible candidates include:
- Women aged 35 and over
- Carriers of sex-linked genetic disorders
- Carriers of single gene defects
- Those with a family history of chromosomal disorders
- Women experiencing recurring pregnancy loss associated with chromosomal concerns
- Those who have had several unsuccessful cycles of IVF where embryos have been transferred
Benefits or advantages of PGD and PGS:
- PGD enables couples to pursue biological children who might not have been able to do so otherwise.
- Performing PGD prior to implantation can reduce the need for amniocentesis later in pregnancy.
- PGD helps reduce the chance of conceiving a child with a genetic factor. However, it cannot completely eliminate this risk. In some cases, further testing done during pregnancy is needed to ascertain if a genetic factor is still possible
Technical aspects of PGD
PGD is performed prior to the embryo being transferred to the uterus. It is important to note that PGD does not replace prenatal testing. Chorionic villi biopsy or amniocentesis is often recommended to confirm the PGD result. The actual process of PGD involves IVF followed by the creation of an aperture in the zona pellucida followed by the aspiration of a single cell from an embryo or polar body from an oocyte. Alternatively trophectoderm cells from the blastocyst can be aspirated. In general PGS at MedFem is achieved by testing single cells of day 3 embryos when it is at the six to eight cell stage. At this stage cells in the embryo is still undifferentiated and therefore capable to become any cell in the body. Aspirating one cell from the embryo will not damage the embryo’s developing potential. Following the biopsy procedure, the evaluation step follows. Biopsied cells are analysed using a procedure called Fluorescent In Situ Hybridization (FISH) or sent for testing (PCR, CGH).
South African law prohibits PGD for gender selection for social reasons.
What is Chromosomal Aneuploidy?
We inherit 23 of our chromosomes from each parent (23 from the egg and 23 from the sperm). When the egg and the sperm come together the zygote is formed and this cell contains 46 chromosomes. The zygote divides to form the embryo and eventually the baby is formed.
Aneuploidy describes a chromosome problem. It means that there are one or a few chromosomes above or below the normal chromosome number. For example, three number 21 chromosomes or trisomy 21 (Down Syndrome) is an example of aneuploidy. The most common aneuploidies are trisomies and extra sex chromosomes.
Live-born children can have trisomy 13, 18, or 21. Trisomy of any other chromosome is usually fatal.
Trisomy 13 (Patau’s syndrome) is characterised by slow growth, cleft lip, small head and chin, and mental retardation. Babies born with trisomy 13 have severe mental retardation and other birth defects such as abnormalities of the head, thumbs, ears, mouth and feet. Most of these babies do not survive beyond the first few months of life.
Edward’s syndrome (Trisomy 18) is marked by severe, variable and mental retardation. The risk for miscarriage in the pregnancy is markedly increased. Trisomy 21 (Down’s syndrome) occurs equally in all ethnic groups, and is closely related to increased maternal age. Down syndrome causes mental retardation and other birth defects, such as heart abnormalities.
Aneuploidy of the sex chromosomes can cause abnormal genital development, sterility, and other growth problems. Males with an XXY aneuploidy have Klinefelter’s syndrome, and have small testes and typically no sperm.
Turner syndrome is caused by the absence of one sex chromosome (45,XO). Affected people can have heart abnormalities, kidney, and infertility problems.
More about Advanced Maternal Age and PGD
The inverse correlation between age and female fertility is well known. Several studies have shown that fertility rates drop in a woman’s mid thirties, decline gradually and fall drastically after 40.
Women aged 20-34 years were found to have 50% of their embryos aneuploid when tested, even when the embryos looked normal by microscopic examination. It has been shown that no significant difference in fertilisation rate is experienced between women age 35 years and 40 years. In contrast, pregnancy rate does differ between these two groups. This gap widens further when delivery rate is considered. The incidence of miscarriage increases from about 25% at age 35, to 33% at age 40 and 50% at age 45. Magli et al recorded that 69% of the embryos of female patients of 36-37 years carried chromosomal abnormalities while the abnormalities increased to 81-90% in patients aged 40 years and older. These findings led to the conclusion that the age declined in female fertility is due to poorer oocyte quality. PGD explains the decrease in fertility rate and the increase in miscarriage and genetic abnormality rate of older women.
It was also found that morphological criteria currently used for assessment of embryo quality might in some cases be misleading. Some of the embryos that appeared morphologically perfect were found to be genetically abnormal while some unattractive embryos were in fact normal. If it was found that the majority embryos of a particular individual are chromosomally abnormal she could turn to an egg donor program. This information may spare the expense and disappointment of repeated IVF failures.
More about Recurrent IVF failures
We can also test for chromosomes 15, 16, 17, and 22. These chromosomes can lead to failed implantation or miscarriage.
It has been found that approximately 59% of embryos tested from patients with recurrent miscarriages were chromosomally abnormal. Finally, women known to have an abnormal genetic makeup of their own were found to have 62% of their embryos aneuploid when tested by FISH.
More Sex-linked Genetic Disorders
Gender determination is performed on transmitted recessive X-linked disorders such as Duchene muscular dystrophy, Lesch-Nylan syndrome, Charcot-Marie-Tooth disease, adrenoleukodystrophy and colour blindness. They are called sex linked diseases because there is an abnormal gene that is carried on the X chromosome. A female receives one X chromosome from her father and one from her mother. She might inherit one defective X chromosome but she will be normal as long the other X chromosome is normal. A female won’t be affected by the disease but she will be a carrier of this disease. The disease could possibly be transmitted to her sons. A male acquires an X chromosome from his mother, and a Y chromosome from his father. If he inherits a faulty X chromosome, he will have the disease. Diseases linked to the Y chromosome are extremely rare.
Sperm FISH studies
Chromosomal abnormalities in sperm may cause infertility and recurrent miscarriages. Often sperm cells are not examined for chromosomal abnormalities. Chromosomal abnormal sperm are able to induce a pregnancy though the likelihood of a full term pregnancy and failed cycles are reduced.
Sperm FISH testing can be considered in patients with multiple unsuccessful Assisted Reproductive cycles, unexplained miscarriages and males with oligo- and asthenozoospermia. It is well known that the incidence of chromosomal anomalies in Oligoteroasthenozoospermic (OTA) males is higher than in the normal population. These patients have a low sperm count, poor morphology and motility. Test results will indicate the incidence of producing abnormal embryos.
There are a few novel indications for which PGD can be used. This includes preimplantation HLA – matching or “the creation of a Saviour Sibling”. Human leukocyte antigen (HLA) matching is done when an affected patient needs matching bone marrow or cord blood for stem cell transplantation. HLA antigens are found on most cells in your body. A well-matched donor is important, and HLA is inherited. A close match would probably a brother or a sister. With the same parents, siblings have a 25% chance of having a close HLA match. When two people share the same Human Leukocyte Antigens ( HLA), they are said to be a “match”. Their tissues are immunologically compatible with each other.
PGD combined with HLA matching allows us to indentify a disease free tissue matched embryo. Therefore PGD with HLA matching not only ensure a healthy baby but also allow matching stem cell transplantation to an affected child.
Single Gene Defects
We have recently formed joined venture collaboration with renowned Genetic Institutes which enable us to identify and test for single gene defects. They are using specialized evaluation techniques which enable them to identify the defective gene. This technique is called PCR (polymerase chain reaction) and CGH (Comparative Genome Hybridisation). These genetic Laboratories are able to develop genetic probes which are custom designed for families.
Some of the genes they are able to detect are listed below.
If the disease of concern in your family is not listed below, we will contact them to determine if PGD is possible.
Genetic Disorder (Gene)
Actin-Nemalin Myopathy (ACTA1)
Adenomatous Polyposis Coli (FAP-APC)
Alagille Syndrome (JAG1)
Aldolase A deficiency (ALDOA)
Alpha Thalassemia (HBA1)
Alpha Thalassemia/Mental Retard (ATRX)
Alpha-1-Antitrypsin Deficiency (AAT)
Alport Syndrome (COL4A5)
ALS: Amyotrophic Lateral Sclerosis 1, (SOD1)
Alzheimer Disease 3 (PSEN1)
Amegakaryocytic Thrombocytopenia, Congenital (CAMT)
Amyloidosis I-Transthyretin (TTR)
Angioedema, Hereditary (C1NH)
Ankylosing spondylitis (Susceptibility to, HLA-B27)
Antithrombin Deficiency (SERPINC1)
Apert Syndrome (FGFR2)
Ataxia Telangiectasia (ATM)
Basal Cell (Gorlin) Synd (PTCH)
Beta Thalassemia (HBB)
Bloom Syndrome (BLM)
Brachydactyly-Type C (GDF5)
Breast Cancer (BRCA1 & 2)
Canavan Disease (ASPA)
Cardiomyopathy, Barth Type Dilated (TAZ)
Cardiomyopathy, Dilated Hypertrophic (MYH7)
Dilated Hypertrophic Cardiomyopathy MYH7
Carnitine-AcylCarn Translocase (SLC25A20)
Ceroid-Lipofuscinoses-Batten Disease (PPT1)
Ceroid-Lipofuscinoses-Finish Type (CLN5)
Ceroid-Lipofuscinoses-Juvenile Type (CLN3)
Charcot Marie Tooth 1A (PMP22)
Charcot Marie Tooth Neuropathy – 2E, (NF-L, NEFL)
Charcot-Marie-Tooth neuropathy 1B (MPZ)
Chronic Granulomatous Disease (CYBB)
Cleidocranial Dysplasia (RUNX2)
Cockayne syndrome type B (CSB; ERCC6)
Colon Cancer (HNPCC; MSH2)
Congenital Adrenal Hyperplasia (CYP21A2 )
Congenital Disorder Glycosylation, 1a – CDG-1a (PMM2)
Congenital Disorder Glycosylation, 1c – CDG-1c (ALG6)
Congenital Disorder Glycosylation, 1e – CDG-1e (DPM1)
Congenital Disorder Glycosylation, 1g – CDG-1g (ALG12)
Congenital Erythropoietic Porphyria (UROS)
Cosman-Cyclic Neutropenia (ELA2)
Crigler Najjar (UGT1A1)
Crouzon Syndrome (FGFR2)
Cystic Fibrosis (CFTR)
Darier Disease (ATP2A2)
Deafness, Recessive – (GJB2 Connexin 26)
Deafness, Recessive – (GJB6 Connexin 30)
Deafness, Recessive (DFBN1)
Denys-Drash Wilms Tumor (WT1)
Desmin Storage Myopathy (DES)
Diamond Blackfan (DBA-RPS19)
Diamond Blackfan (DBA2) Not RPS19
Duchenne muscular dystrophy (DMD)
Dyskeratosis Congenita (DKC1)
Dystrophia Myotonica-1 (DMPK) CTGrpt
Dystrophia Myotonica-2 (DM2; PROMM) CCTGrpt
Ectodermal Dysplasia I EDA1
Emery-Dreifuss X-Linked Muscular Dystrophy
Emery-Dryfuss AutoDom Muscular Dystrophy (LMNA)
Epidermolysis Bullosa (KRT5)
Epidermolysis Bullosa Simplex KRT14
Epidermolysis Bullosa/Pyloric Atresia – ITGB4
Epidermolysis Dystrophic Bullosa-COL7A1
Epidermolytic Hyperkeratosis (KRT10)
Facioscapulohumeral Dystrophy (FSHD)
Factor 13 Deficiency (F13A1)
Familial Dysautonomia (IKBKAP)
Familial Exudative Vitreoretinopathy FZD4
Fanconi Anemia A (FANCA)
Fanconi Anemia C (FANCC)
Fanconi Anemia F (FANC F)
Fanconi Anemia J (FANCJ, BRIP1)
Fanconia Anemia G (FANCG)
Fragile X (FMR1)
Friedreich Ataxia I (FRDA)
Gastric Cancer, Cadherin-E-1 (CDH1)
Gaucher Disease (GBA)
Gerstmann-Straussler Disease (PRNP)
Glutaric Acidemia 2A (ETFA)
Glycine Encephalopathy GLDC 80% (NKH)
Glycogen Storage Disease I, Von Girke – GSD1a (G6PC)
Glycogen Storage Disease 2, Pompe – GSD2 (GAA)
GM1 Gangliosidosis, Morquio (GLB1)
Hemophilia A (Factor 8)
Hemophilia B (Factor 9)
Hereditary Hemmorrhagic Telangietasia Type 1 (HHT1)
Histiocytosis, Hemophagocytic Lympho- (HLH; PRF1)
HLA DRBeta1 Class II MHC (HLA DRB1*)
HLA-Histocompatability, Transplantation Matching (HLA)
Hunter syndrome (IDS)
Huntington Disease (HD)
Hurler Syndrome (MPSI-IDUA)
Hyper IgM (CD40-ligand; TNFSF5)
Hypokalemic periodic paralysis (SCN4A-HYPP)
Hypophosphatemic VitD Rickets
Icthyosis, X-Steroid Sulf Def
Icthyosis.Congenital, Harlequin (ABCA12)
Incontinentia Pigmenti (NEMO)
Joubert Syndrome (AHI1)
KELL Antigen (KEL)
Kennedy-Spinal bulbar (AR)
Leber Retinal Congenital Amaurosis-I (GUCY2D)
Leber Retinal Congenital Amaurosis-X (CEP290)
Leukemia, Acute Lymphocytic, Transplantation (ALL)
Leukemia, Acute Myelogenous, Transplantation (AML)
Leukemia, Chronic Myelogenous, Transplantation (CML)
Leukocyte Adhesion Deficiency (ITGB2)
Li-Fraumeni Syndrome (TP53)
Limb Girdle MD (FKTN)
Long-Chain-AcylCoA Dehydrogenase (LCHAD:HADHA)
Lymphoproliferative Disorder, X-linked (SH2D1A)
Machado-Joseph Spinocerebellar Ataxia-3 (SCA3)
Macular Dystr-Best Vitelliform (VMD2)
Maple Syurp Urine Dz E1-Beta (BCKDHB)
Marfan Syndrome (FBN1)
Meckel-Gruber Syndrome-3 (MKS3)
Merosin-deficient congenital muscular dystrophy type 1A (MDC1A)
Metachromatic Leukodystrophy (ARSA)
Methylcobalamin G Deficiency (MTR)
Methylmalonic Acidemia (MUT)
Mitochondrial Myopathy-Complex I (NDUFS4)
Mucolipidosis 2, I Cell (GNPTAB)
Multiple Endocrine Neoplasia 1 (MEN1)
Multiple Endocrine Neoplasia 2 MEN2 (RET)
Multiple Extostoses (EXT1)
Multiple Extostoses (EXT2)
Myasthenia Gravis (CHRNE)
Myotubular Myopathy X-Linked (MTM)
NEMO immunodeficiency (IKBKG)
Nephrosis – Finnish (NPHS1)
Neurofibromatosis 1 (NF1)
Neurofibromatosis 2 (NF2)
Niemann Pick – Type A (SMPD1)
Niemann Pick – Type C (NPC1)
NonKetotic Hyperglycinemia (GLDC)
Occulocutaneous Albinism II- (OCA2)
Occulocutaneous Albinism I, OCA1 (TYR)
Ocular Albinism-X Linked (GPR143)
Oculodentodigital Dysplasia (GJA1)
Optic Atrophy 1 (OPA1)
Ornithine transcarbamylase deficiency (OTC)
Osteogenesis Imper II/IV & Chondrodysplasias(COL1A2)
Osteogenesis Imperfecta I (COL1A1)
Pachyonychia Congenita (KRT6A)
Pachyonychia Congenita (KRT16A)
Pancreatitis, Chronic Calcific (PRSS1) Pancreatitis-Hereditary (KEL)
Pelizaeus-Merzbacher, X-linked (PLP1)
Periventricular Heteropia (FLNA)
Pendred Syndrome (SLC264A)
Persistent Hyperinsulinemic Hypoglycemia of Infancy (ABCC8)
Pfeiffer Syndrome (FGFR2)
Phenylketonuria PKU (PAH)
Polycystic Kidney Disease (PKD1)
Polycystic Kidney Disease (PKD2)
Polycystic Kidney Disease, Recessive (PKHD1)
Pompe, Glycogen Storage Disease 2, GSD2 (GAA)
Propionic Acidemia (PCCA)
Pseudohypoparathyroidism 1a (GNAS1)
Retinitis Pigmentosa (RHO)
Retinitis Pigmentosa adRP10 (IMPDH1)
Retinitis Pigmentosa X-linked (RPGR)
Retinoblastoma 1 (RB1)
Rett Syndrome (MECP2)
Rhesus blood group D (RHD)
Rhizomelic Chondrodysplasia Punctata (RCDP1)
Rothmund-Thompson Syndrome (RECQLA)
Sacral Agenesis (HLXB9)
Sanfilippo A (MPSIIIA)
Sanfillipo B (MPSIIIB) (NAGLU)
Sathre-Chotzen Craniosynostosis (TWIST)
Severe Comb Immunodef (SCID)
Shwachman-Diamond Syndrome (SBDS)
Sickle Cell (HBB)
Simpson-Golabi-Behmel Syndrome (GPC3)
Sorsby Fundus Dystrophy (TIMP3)
Spinal muscular atrophy SMA (SMN1)
Spinocerebellar Ataxia-1, SCA1 (ATNX1)
Spinocerebellar ataxia-2, SCA2 (ATXN2)
Spinocerebellar Ataxia-3, Machado-Joseph (SCA3)
Spinocerebellar Ataxia-7 (ATXN7)
Spondyloepiphyseal dysplasia, congenital (SEDc)
Steroid Sulfatase Deficiency (STS)
Stomach-Ovarian-Endometrial Cancer (CDH1)
Supravalvular Aortic Stenosis (ELN)
Surfactant-Pulmonary B (SFTPB)
Thrombocytopenia with Beta-Thalassemia (GATA1)
Torsion dystonia (DYT1)
Treacher Collins (TCOF1)
Transplantation-BoneMarrow-StemCell (HLA locus)
Tuberous Sclerosis 1 (TSC1)
Tuberous Sclerosis 2 (TSC2)
Usher Syndrome (MYO7A)
VanderWoude -Popliteal Pterygium (IRF6)
Von Hippel-Lindau Disease (VHL)
Waardenburg Syndrome Type II (MITF)
Waardenburg Syndrome-I/III (PAX3)
West Syndrome (ARX)
Wilms Tumor (WT1)
Wiskott-Aldrich Syndrome (WAS)
Wolman Lipase A (LIPA)
Zellweger Peroxisome Disease (PEX1)
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