Principles guiding embryo selection following genome-wide haplotyping of preimplantation embryos

• Published in: Human reproduction (Oxford) 2017-03, Vol.32 (3), p.687-697
• Main Authors: Dimitriadou, Eftychia, Melotte, Cindy, Debrock, Sophie, Esteki, Masoud Zamani, Dierickx, Kris, Voet, Thierry, Devriendt, Koen, de Ravel, Thomy, Legius, Eric, Peeraer, Karen, Meuleman, Christel, Vermeesch, Joris Robert
• Format: Article
• Language: English
• Subjects: Blastocyst - physiology; Chromosome Disorders - diagnosis; Embryo Culture Techniques; Embryo Transfer - ethics; Genetic Carrier Screening; Haplotypes; Humans; Practice Guidelines as Topic; Preimplantation Diagnosis - ethics
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/dex011

Abstract STUDY QUESTION How to select and prioritize embryos during PGD following genome-wide haplotyping? SUMMARY ANSWER In addition to genetic disease-specific information, the embryo selected for transfer is based on ranking criteria including the existence of mitotic and/or meiotic aneuploidies, but not carriership of mutations causing recessive disorders. WHAT IS KNOWN ALREADY Embryo selection for monogenic diseases has been mainly performed using targeted disease-specific assays. Recently, these targeted approaches are being complemented by generic genome-wide genetic analysis methods such as karyomapping or haplarithmisis, which are based on genomic haplotype reconstruction of cell(s) biopsied from embryos. This provides not only information about the inheritance of Mendelian disease alleles but also about numerical and structural chromosome anomalies and haplotypes genome-wide. Reflections on how to use this information in the diagnostic laboratory are lacking. STUDY DESIGN, SIZE, DURATION We present the results of the first 101 PGD cycles (373 embryos) using haplarithmisis, performed in the Centre for Human Genetics, UZ Leuven. The questions raised were addressed by a multidisciplinary team of clinical geneticist, fertility specialists and ethicists. PARTICIPANTS/MATERIALS, SETTING, METHODS Sixty-three couples enrolled in the genome-wide haplotyping-based PGD program. Families presented with either inherited genetic variants causing known disorders and/or chromosomal rearrangements that could lead to unbalanced translocations in the offspring. MAIN RESULTS AND THE ROLE OF CHANCE Embryos were selected based on the absence or presence of the disease allele, a trisomy or other chromosomal abnormality leading to known developmental disorders. In addition, morphologically normal Day 5 embryos were prioritized for transfer based on the presence of other chromosomal imbalances and/or carrier information. LIMITATIONS, REASONS FOR CAUTION Some of the choices made and principles put forward are specific for cleavage-stage-based genetic testing. The proposed guidelines are subject to continuous update based on the accumulating knowledge from the implementation of genome-wide methods for PGD in many different centers world-wide as well as the results of ongoing scientific research. WIDER IMPLICATIONS OF THE FINDINGS Our embryo selection principles have a profound impact on the organization of PGD operations and on the information that is transferred among the