Balkan Journal of Medical Genetics

PRE-IMPLANTATION GENETIC DIAGNOSIS FOR β-THALASSEMIA, SICKLE CELL SYNDROMES AND CYSTIC FIBROSIS IN GREECE
Traeger-Synodinos J1,*, Vrettou C1, Tzetis M1, Palmer G2, Davis S3, Mastrominas M3, Kokali G4, Pandos K4, Kanavakis E1
*Corresponding Author: : Dr. Joanne Traeger-Synodinos, Medical Genetics, Athens University, Choremio Research Laboratory, St. Sophia’s Children’s Hospital, Thivon and Levadias Streets, Athens 11527, Greece; Tel.: +30-210-746-7461; Fax: +30-210-779-5553; E-mail: jtraeger@cc.uoa.gr
page: 25

INTRODUCTION

Pre-implantation genetic diagnosis (PGD) represents an alternative to prenatal diagnosis (PND), originally developed to allow selection of unaffected in vitro fertilized (IVF) embryos for establishing pregnancies in couples at risk for transmitting a genetic disorder, thus avoiding the need to terminate affected on-going pregnancies [1]. More than any other procedure in genetic diagnostic services PGD requires close collaboration with experts in reproductive medicine, as well as genetics, and standard assisted reproductive treatment is required prior to and following embryo biopsy and genetic diagnosis [2,3]. There are potentially three types of cells suitable for PGD analysis including polar bodies (PBs) from the oocyte/ zygote stage, blastomeres from cleavage-stage embryos, or trophectoderm cells from blastocysts, and the expertise of an embryologist is fundamental to ensure a successful biopsy while maintaining embryo viability [2]. Blastomere biopsy is the current method of choice of most centers offering clinical PGD cycles [4].
The β hemoglobinopathies and cystic fibrosis (CF) are the most common monogenic disorders in Greece, with a carrier incidence of approximately 10 and 5%, respectively [5-7]. Prevention programs involving PND are well established for both diseases, but for some couples PGD may be a more appropriate option. These include carrier couples with infertility who are resorting to assisted reproduction to initiate a pregnancy, couples who have experienced termination of at least one affected pregnancy following a prenatal diagnosis, and couples who have an ethical or religious objection to pregnancy termination [8].
Protocols for genotyping single-cells for monogenic disorders are based on the polymerase chain reaction (PCR). More than a decade of experience has highlighted several inherent pitfalls associated with single-cell DNA amplification [2,9] These include potential sample contamination, total PCR failure, and allelic drop-out (ADO) when one of the alleles fails to amplify to detectable levels, all of which should be minimized for any PGD PCR protocol prior to clinical application. In addition, the chosen method must reliably and accurately characterize the genotype of the embryo relative to the disorder under investigation. In Greece, both β-thal and CF are caused by a wide range of mutations [5-7]. Thus, for each disease, we elected to develop PGD analytical protocols applicable to a wide range of affected genotypes (outlined in this review), rather than having to develop case-specific protocols for each PGD performed. In addition, many practical aspects of applying PGD within the context of a preventive genetic service for common recessive diseases, are summarized, highlighting approaches for improvement, pitfalls and overall limitations.

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