4.6 Article

Expanded clinical validation of Haploseek for comprehensive preimplantation genetic testing

Journal

GENETICS IN MEDICINE
Volume 23, Issue 7, Pages 1334-1340

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-021-01145-6

Keywords

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Funding

  1. Shaare Zedek Mirsky intramural grant
  2. Hebrew University of Jerusalem Center for Interdisciplinary Data Science Research (CIDR) [3035000322]

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This study extended the Haploseek method by incorporating DNA from embryo grandparents and conducting systematic validation on 151 embryo biopsies from 27 clinical PGT cases. Results demonstrated that Haploseek accurately predicted haplotypes and CNVs in all cases, making it suitable for standard clinical PGT applications for various genetic disorders.
Purpose We previously developed Haploseek, a method for comprehensive preimplantation genetic testing (PGT). However, some key features were missing, and the method has not yet been systematically validated. Methods We extended Haploseek to incorporate DNA from embryo grandparents and to allow testing of variants on chromosome X or in regions where parents share common haplotypes. We then validated Haploseek on 151 embryo biopsies from 27 clinical PGT cases. We sequenced all biopsies to low coverage (0.2x), and performed single-nucleotide polymorphism (SNP) microarray genotyping on the embryos' parents and siblings/grandparents. We used the extended Haploseek to predict chromosome copy-number variants (CNVs) and relevant variant-flanking haplotypes in each embryo. We validated haplotype predictions for each clinical sample against polymerase chain reaction (PCR)-based PGT case results, and CNV predictions against established commercial kits. Results For each of the 151 embryo biopsies, all Haploseek-derived haplotypes and CNVs were concordant with clinical PGT results. The cases included 17 autosomal dominant, 5 autosomal recessive, and 3 X-linked monogenic disorders. In addition, we evaluated 1 Robertsonian and 2 reciprocal translocations, and 17 cases of chromosome copy-number counting were performed. Conclusion Our results demonstrate that Haploseek is clinically accurate and fit for all standard clinical PGT applications.

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