Atlas of Preimplantation Genetic Diagnosis

296 Pages·2011·7.335 MB·English

by  Yury Verlinsky, Anver Kuliev

Atlas of
PREIMPLANTATION
GENETIC DIAGNOSIS
Second Edition

Atlas of
PREIMPLANTATION
GENETIC DIAGNOSIS
Second Edition
Yury Verlinsky PhD
and
Anver Kuliev MD PhD
Reproductive Genetics Institute
Chicago, Illinois

informa
healthcare
New York London
CRC Press
Taylor & Francis Group
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Version Date: 20130415
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Contents
List of contributors vii
Acknowledgment viii
Preface ix
Foreword xiii
Professor Robert G Edwards
Introduction I
SECTION I Review of Current Methods and Experience in Preimplantation Genetic 5
Diagnosis
1 Normal and abnormal human preimplantation development in relation to preimplantation 7
genetic diagnosis and establishment of embryonic stem cells
Introduction 7
Oocytes at different stages of meiosis I 7
Oocytes at metaphase II and variations in first polar body formation 8
First polar body morphology in relation to chromosomal abnormality in oocytes 8
Oocytes following fertilization and second polar body extrusion 10
Normally and abnormally cleaving embryos I I
Normal and abnormal blastocyst formation 11

Establishment of human embryonic stem cells 11
References 12
2 Micromanipulation and biopsy of polar bodies and blastomeres 15
First polar body removal 18
Intracytoplasmic sperm injection 19
First and second polar body removal 20
Blastomere removal 21
Blastocyst biopsy 22
References 22
3 Nuclear transfer techniques for preimplantation diagnosis and prospect for artificial 23
gamete formation
v
ATLAS OF PREIMPLANTATION GENETIC DIAGNOSIS
Visualization of polar body and blastomere chromosomes 23
Sperm duplication 26
Development of artificial human gametes in vitro 26
References 27
4 Preimplantation diagnosis for aneuploidies 29
Introduction 29
Preparation of polar bodies and blastomeres for fluorescence in situ hybridization 3 I
analysis
Pretreatment, probe application, hybridization and washing 34
Fluorescent signal evaluation 36
Chromosomal abnormalities in polar bodies 37
Chromosomal abnormalities in cleaving embryos 39
References 40
5 Preimplantation diagnosis for translocations 43
References 47
6 Preimplantation diagnosis for single-gene disorders 49
Updated procedure of single-cell DNA analysis for PGD of single-gene disorders 49
Diagnostic accuracy 53
PGD for specific genetic disorders 55
Conclusion 60
References 61
7 Future perspectives for preimplantation diagnosis 63
Improving accuracy of PGD for single-gene disorders 63
Preconception diagnosis for paternally derived genetic disorders 64
Developments in sampling procedures 64
Towards PCR-based karyotyping 64
Production of male and female gametes from human somatic cells 65
Stem cell transplantation and availability of human embryonic stem cells 65
Introduction of PGD as the future IVF standard 66
References 67
SECTION II Preimplantation Genetic Diagnosis Illustrated 71
1 Normal and abnormal human preimplantation development in relation to preimplantation 73
genetic diagnosis and establishment of embryonic stem cells
2 Micromanipulation and biopsy of polar bodies and blastomeres 103
3 Nuclear transfer techniques for preimplantation diagnosis and prospect for artificial I 17
gamete formation
4 Preimplantation diagnosis for aneuploidies 141
5 Preimplantation diagnosis for translocations 179
6 Preimplantation diagnosis for single-gene disorders 213
Index 281
vi
List of contributors
All the contributors are affiliated with the
Reproductive Genetics Institute, 2825 N. Halsted Street,
Chicago, IL 60657, USA
Jeanine Cieslak-Janzen MLT
Embryology and chromosomal disorders
Vasily Galat PhD
Artificial gametes and visualization of blastomere
chromosomes
Veleriy Kuznyetsov PhD
Sperm duplication and visualization of blastomere
chromosomes
Svetlana Rechitsky PhD
Single-gene disorders
Nick Strelchenko PhD
Embryonic stem cells
Oleg Verlinsky MS
Single-gene disorders
Acknowledgment
We are indebted to our colleagues in the DNA, FISH and embryology laboratories:
T Sharapova, S Ozen, K Lazyuk, G Wolf Y Illkevitch, V Koukharenko, Z Zlatapolsky
and I Kirillova, and also to our genetic counselors, C Lavin, R Beck, R Genoveze and
D Pauling for their participation in acquisition of the data and technical assistance.
Preface
Preimplantation genetic diagnosis [PGD], intro­ Because many carriers of balanced translocations
duced in 1990 as an experimental procedure1'2, has have a poor chance of having an unaffected preg­
now been developed into a practical tool for avoid­ nancy, PGD has a clear advantage over the tradi­
ing the birth of affected children. It represents a tional prenatal diagnosis in assisting these couples to
valuable complement to traditional prenatal diagno­ establish an unaffected pregnancy and deliver a child
sis and a clinical option in reproductive medicine. free from the disorder. Current developments and
The number of unaffected children born following application of nuclear transfer techniques (Chapter
PGD is already over 10003, a testimony to the accu­ 3), and microarray technology may further
racy and safety of PGD, which is now being used to contribute to improvements of PGD for transloca­
establish a potential donor progeny for the stem cell tions (Chapter 5].
treatment of siblings4. PGD has allowed hundreds of The natural extension of PGD’s ability to allow
‘at risk’ couples, not only to avoid producing transfer of euploid embryos is its positive impact on
offspring with genetic disorders, but also, more the liveborn pregnancy outcome910. This is espe­
importantly, to have unaffected healthy babies of cially applicable to poor-prognosis in vitro fertiliza­
their own, without facing the risk of pregnancy tion (IVFj patients, including prior IVF failures and
termination after traditional prenatal diagnosis3-6'7. those with a maternal age over 37. The introduction
The technique was first applied to pre-existing of commercially available five-color probes in
Mendelian diseases, such as cystic fibrosis and X- 1998-1999 led to the present accumulated experi­
linked disorders, but initially did not seem to have ence of approximately 5000 clinical cycles for aneu­
any practical value. However, after the introduction ploidy testing. This has resulted in the birth of close
of fluorescence in situ hybridization (FISH) analysis to 1000 aneuploidy-free children. The overall preg­
in 1993-1994 for PGD of chromosomal disorders, nancy rate per transfer is much higher than in IVF
the number of PGD cycles began to double annually, patients of comparable age. Widespread confirma­
yielding more than 100 unaffected children by 1996. tion of these results would indicate that the current
Although the accuracy of PGD for aneuploidies has IVF practice of transferring embryos based solely on
improved considerably, there is still the risk of misdi­ morphological criteria is inefficient and in need of
agnosis due to a high prevalence of mosaicism at the revision, given that half of these embryos are chro-
cleavage stage7,8. A sequential sampling of both mosomally abnormal and would compromise
oocytes and the resulting embryos may improve the outcome (Chapter 4). A high prevalence of aneu­
accuracy of aneuploidy testing, and may also allow ploidies in oocytes and embryos may also affect the
the detection of embryos with uniparental disomies accuracy of PGD for single-gene disorders7, making
(Chapter 4). aneuploidy testing an important part of PGD for
Application of PGD increased further when the mendelian diseases and preimplantation testing for
ability to detect translocations became possible in human leukocyte antigen (HLA) typing (Chapter 6).
1996, first using locus-specific FISH probes and then Further expansion of PGD occurred in 1999,
the more widely available subtelomeriC probes8. when the technique was applied to late-onset
ATLAS OF PREIMPLANTATION GENETIC DIAGNOSIS
diseases with a genetic predisposition, a novel indi­ Since the first edition of this Atlas, PGD has also
cation that had not been previously considered for been improved, involving macromanipulation proce­
the traditional prenatal diagnosis11,,z. For patients dures, including the originally introduced microma­
with an inherited pathological predisposition this nipulation techniques to remove the first and second
option provided realistic grounds for undertaking polar body and biopsy cleaving embryos, together
pregnancy, with a reasonable chance of unaffected with other related methods, such as intracytoplasmic
offspring. Prospective parents at such risk should be sperm injection, which has become an integral part
made aware of this emerging option (Chapter 6).
of PGD for single-gene disorders (Chapter 2). The
Another unique option that can now be consid­
techniques have been reproduced in more than 50
ered concerns HLA typing during PGD which was
PGD centers all over the world. These have
introduced in 2000 (Chapter 6). This option has not
performed more than 6000 clinical cycles to date,
been considered during traditional prenatal diagno­
resulting in the birth of more than 1000 apparently
sis, but with PGD it offers, not only preventative
unaffected children, with an overall congenital
technology to avoid affected offspring, but also a
malformation rate no different from that of the
new method for treating (older) siblings with
general population14. More than two-thirds of these
congenital or acquired bone marrow diseases. This
clinical cycles were performed in the US, from which
approach was first applied to souples desiring an
the largest number (over 2000 cycles) has been
unaffected (younger) child free from the disorder in
contributed by our center.
the older sibling4. In addition to diagnosis to ensure
a genetically normal embryo, HLA-matched, unaf­ With the greatly improved accuracy of genetic
fected embryos were replaced. At delivery, cord analysis and indications expanding well beyond those
blood (otherwise to be discarded) was gathered for for prenatal diagnosis, more than 1000 PGD cycles
stem cell transplantation, resulting in complete cure are now performed annually. Experience during the
in the case of a sibling with Fanconi anemia. This past 2 years has resulted in the birth of nearly the
approach was then also used without testing of the same number of children as during the entire preced­
causative gene, with the sole purpose of finding ing decade. The list of conditions for which PGD is
matching HLA progeny for a source of stem cell performed is being extended rapidly, and presently
transplantation for affected siblings with congenital includes single-gene disorders presented at birth,
or acquired bone marrow disease or cancer13. latc-onset disorders, HLA genotyping and chromoso­
Together with progress in the establishment of mal abnormalities. PGD offers particular advantages
embryonic stem cells, this may contribute to the not attainable with traditional prenatal diagnosis
development and application of stem cell therapy, so including avoidance of clinical pregnancy termina­
a specific discussion in the second edition of this
tion, which is especially attractive for couples carry­
Atlas (Chapter 7) will be devoted to this issue.
ing translocations, couples at risk for producing
As in the previous edition, Chapter 1 details
offspring with common diseases of autosomal domi­
normal and abnormal preimplantation development,
nant or recessive etiology, and, finally, for couples
including oocyte maturation and fertilization, cleav­
age stage and blastocyst formation. In addition to wishing not only to have an unaffected child, but also
an HLA-compatible cord blood donor for treatment
observations on the morphological parameters of
of an older sibling with a congenital disorder. Yet the
polar bodies and pronuclear formation, recent data
greatest numerical impact of PGD is in standard
on the relationship between morphological parame­
assisted reproduction, where improved IVF effi­
ters and chromosomal status are presented, offering
ciency through aneuploidy testing is evolving to
the future possibility of predicting the developmen­
become standard practice.
tal potential of embryos without chromosomal
analysis. This chapter is of particular relevance for Finally, the second edition of this Atlas presents
PGD, because appropriate selection of the material for the first time progress in the use of PGD as a
for genetic analysis at each stage of preimplantation source of embryonic stem cell (ESC) lines and future
development will affect the test results and their developments in the use of nuclear transfer tech­
interpretation, avoiding misdiagnosis and achieving niques for improving PGD, and producing human
the highest accuracy and reliability of PGD. gametes.
X