Identity-by-state-based haplotyping expands the application of comprehensive preimplantation genetic testing

• Published in: Human reproduction (Oxford) 2020-03, Vol.35 (3), p.718-726
• Main Authors: Ding, Jia, Dimitriadou, Eftychia, Tšuiko, Olga, Destouni, Aspasia, Melotte, Cindy, Van Den Bogaert, Kris, Debrock, Sophie, Jatsenko, Tatjana, Esteki, Masoud Zamani, Voet, Thierry, Peeraer, Karen, Denayer, Ellen, Vermeesch, Joris Robert
• Format: Article
• Language: English
• Subjects: Child; Female; Genetic Testing; Haplotypes; Humans; Pregnancy; Preimplantation Diagnosis; Prospective Studies; Retrospective Studies
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/dez285

Abstract STUDY QUESTION Is it possible to haplotype parents using parental siblings to leverage preimplantation genetic testing (PGT) for monogenic diseases and aneuploidy (comprehensive PGT) by genome-wide haplotyping? SUMMARY ANSWER We imputed identity-by-state (IBS) sharing of parental siblings to phase parental genotypes. WHAT IS KNOWN ALREADY Genome-wide haplotyping of preimplantation embryos is being implemented as a generic approach for genetic diagnosis of inherited single-gene disorders. To enable the phasing of genotypes into haplotypes, genotyping the direct family members of the prospective parent carrying the mutation is required. Current approaches require genotypes of either (i) both or one of the parents of the affected prospective parent or (ii) an affected or an unaffected child of the couple. However, this approach cannot be used when parents or children are not attainable, prompting an investigation into alternative phasing options. STUDY DESIGN, SIZE, DURATION This is a retrospective validation study, which applied IBS-based phasing of parental haplotypes in 56 embryos derived from 12 PGT families. Genome-wide haplotypes and copy number profiles generated for each embryo using the new phasing approach were compared with the reference PGT method to evaluate the diagnostic concordance. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included 12 couples with a known hereditary genetic disorder, participating in the comprehensive PGT program and with at least one parental sibling available (e.g. brother and/or sister). Genotyping data from both prospective parents and the parental sibling(s) were used to perform IBS-based phasing and to trace the disease-associated alleles. The outcome of the IBS-based PGT was compared with the results of the clinically implemented reference haplotyping-based PGT method. MAIN RESULTS AND THE ROLE OF CHANCE IBS-based haplotyping was performed for 12 PGT families. In accordance with the theoretical prediction of allele sharing between sibling pairs, 6 out of 12 (50%) couples or 23 out of 56 embryos could be phased using parental siblings. In families where phasing was possible, haplotype calling in the locus of interest was 100% concordant between the reference PGT method and IBS-based approach using parental siblings. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION Phasing of parental haplotypes will only be possible when the disease locus lies in an informative region (categorized as IBS1). Phasi