Genome-wide karyomapping accurately identifies the inheritance of single-gene defects in human preimplantation embryos in vitro

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Abstract

Purpose:

Our aim was to compare the accuracy of family- or disease-specific targeted haplotyping and direct mutation-detection strategies with the accuracy of genome-wide mapping of the parental origin of each chromosome, or karyomapping, by single-nucleotide polymorphism genotyping of the parents, a close relative of known disease status, and the embryo cell(s) used for preimplantation genetic diagnosis of single-gene defects in a single cell or small numbers of cells biopsied from human embryos following in vitro fertilization.

Methods:

Genomic DNA and whole-genome amplification products from embryo samples, which were previously diagnosed by targeted haplotyping, were genotyped for single-nucleotide polymorphisms genome-wide detection and retrospectively analyzed blind by karyomapping.

Results:

Single-nucleotide polymorphism genotyping and karyomapping were successful in 213/218 (97.7%) samples from 44 preimplantation genetic diagnosis cycles for 25 single-gene defects with various modes of inheritance distributed widely across the genome. Karyomapping was concordant with targeted haplotyping in 208 (97.7%) samples, and the five nonconcordant samples were all in consanguineous regions with limited or inconsistent haplotyping results.

Conclusion:

Genome-wide karyomapping is highly accurate and facilitates analysis of the inheritance of almost any single-gene defect, or any combination of loci, at the single-cell level, greatly expanding the range of conditions for which preimplantation genetic diagnosis can be offered clinically without the need for customized test development.

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Most cited references 12

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Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial.

Kathleen M. Upham, Nathan R Treff, Deanne Taylor … (2013)

To determine whether blastocyst biopsy and rapid quantitative real-time polymerase chain reaction (qPCR)-based comprehensive chromosome screening (CCS) improves in vitro fertilization (IVF) implantation and delivery rates. Randomized controlled trial. Academic reproductive medicine center. Infertile couples in whom the female partner (or oocyte donor) is between the ages of 21 and 42 years who are attempting conception through IVF. Embryonic aneuploidy screening. Sustained implantation and delivery rates. We transferred 134 blastocysts to 72 patients in the study (CCS) group and 163 blastocysts to 83 patients in the routine care (control) group. Sustained implantation rates (probability that an embryo will implant and progress to delivery) were statistically significantly higher in the CCS group (89 of 134; 66.4%) compared with those from the control group (78 of 163; 47.9%). Delivery rates per cycle were also statistically significantly higher in the CCS group. Sixty one of 72 treatment cycles using CCS led to delivery (84.7%), and 56 of 83 (67.5%) control cycles ultimately delivered. Outcomes were excellent in both groups, but use of CCS clearly improved patient outcomes. Blastocyst biopsy with rapid qPCR-based comprehensive chromosomal screening results in statistically significantly improved IVF outcomes, as evidenced by meaningful increases in sustained implantation and delivery rates. NCT01219283. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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Karyomapping: a universal method for genome wide analysis of genetic disease based on mapping crossovers between parental haplotypes.

Alan Handyside, Alan Thornhill, Brian D Mariani … (2010)

The use of genome wide single nucleotide polymorphism (SNP) arrays for high resolution molecular cytogenetic analysis using a combination of quantitative and genotype analysis is well established. This study demonstrates that by Mendelian analysis of the SNP genotypes of the parents and a sibling or other appropriate family member to establish phase, it is possible to identify informative loci for each of the four parental haplotypes across each chromosome and map the inheritance of these haplotypes and the position of any crossovers in the proband. The resulting 'karyomap', unlike a karyotype, identifies the parental and grandparental origin of each chromosome and chromosome segment and is unique for every individual being defined by the independent segregation of parental chromosomes and the pattern of non-recombinant and recombinant chromosomes. Karyomapping, therefore, enables both genome wide linkage based analysis of inheritance and detection of chromosome imbalance where either both haplotypes from one parent are present (trisomy) or neither are present (monosomy/deletion). The study also demonstrates that karyomapping is possible at the single cell level following whole genome amplification and, without any prior patient or disease specific test development, provides a universal linkage based methodology for preimplantation genetic diagnosis readily available worldwide.

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The origin and impact of embryonic aneuploidy.

Dagan Wells, María Enciso, Jonas Sarasa … (2013)

Despite the clinical importance of aneuploidy, surprisingly little is known concerning its impact during the earliest stages of human development. This study aimed to shed light on the genesis, progression, and survival of different types of chromosome anomaly from the fertilized oocyte through the final stage of preimplantation development (blastocyst). 2,204 oocytes and embryos were examined using comprehensive cytogenetic methodology. A diverse array of chromosome abnormalities was detected, including many forms never recorded later in development. Advancing female age was associated with dramatic increase in aneuploidy rate and complex chromosomal abnormalities. Anaphase lag and congression failure were found to be important malsegregation causing mechanisms in oogenesis and during the first few mitotic divisions. All abnormalities appeared to be tolerated until activation of the embryonic genome, after which some forms started to decline in frequency. However, many aneuploidies continued to have little impact, with affected embryos successfully reaching the blastocyst stage. Results from the direct analyses of female meiotic divisions and early embryonic stages suggest that chromosome errors present during preimplantation development have origins that are more varied than those seen in later pregnancy, raising the intriguing possibility that the source of aneuploidy might modulate impact on embryo viability. The results of this study also narrow the window of time for selection against aneuploid embryos, indicating that most survive until the blastocyst stage and, since they are not detected in clinical pregnancies, must be lost around the time of implantation or shortly thereafter.

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Author and article information

Journal

Journal ID (nlm-ta): Genet Med

Journal ID (iso-abbrev): Genet. Med

Title: Genetics in Medicine

Publisher: Nature Publishing Group

ISSN (Print): 1098-3600

ISSN (Electronic): 1530-0366

Publication date (Print): November 2014

Publication date (Electronic): 08 May 2014

Volume: 16

Issue: 11

Pages: 838-845

Affiliations

[1 ]Illumina , Cambridge, UK

[2 ]Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center , Riyadh, Saudi Arabia

[3 ]Reprogenetics , Livingston, New Jersey, USA

[4 ]Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Maastricht University Medical Centre , Maastricht, The Netherlands

[5 ]GROW, School for Oncology and Developmental Biology, University of Maastricht , Maastricht, The Netherlands

[6 ]Department of Clinical Genetics, Maastricht University Medical Center , Maastricht, The Netherlands

[7 ]Preimplantation Genetics, Melbourne IVF , East Melbourne, Victoria, Australia

[8 ]Reprogenetics UK, Institute of Reproductive Sciences , Oxford, UK

[9 ]The Bridge Centre , London, UK

Author notes

[* ]( ahandyside@ 123456illumina.com )

Article

Publisher Item ID: gim201445

DOI: 10.1038/gim.2014.45

PMC ID: 4225458

PubMed ID: 24810687

SO-VID: 4a885126-478d-4cbf-8dcd-12c5d2151098

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Genome-wide karyomapping accurately identifies the inheritance of single-gene defects in human preimplantation embryos in vitro

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Abstract

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Results:

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Arabidopsis genomics

Most cited references 12

Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial.

Karyomapping: a universal method for genome wide analysis of genetic disease based on mapping crossovers between parental haplotypes.

The origin and impact of embryonic aneuploidy.

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