Preimplantation genetic screens

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Science  25 Sep 2015:
Vol. 349, Issue 6255, pp. 1423
DOI: 10.1126/science.aad4803

Although our knowledge of genetic abnormalities that cause health disorders is expanding, the pace of discovering cures for genetic diseases is not nearly as fast. However, technologies applicable to preventing heritable genetic diseases have been developing, among them so-called “next-generation sequencing.” This efficient and inexpensive means to sequence DNA has revolutionized the study of genomics and could play a major role in future preimplantation genetic screening approaches. It may even improve screening during early pregnancy.


“…it should be possible to prevent the occurrence of…single-gene disorders in children…”

For 25 years, preimplantation genetic diagnosis has been used in circumstances where there is a high risk of a specific genetic defect in an embryo created by in vitro fertilization (IVF). If one or both genetic parents have a known genetic defect, testing can be performed on a single cell from an IVF embryo to determine whether it would be affected with a serious disorder. For many people undergoing IVF, new diagnostics are welcome, less risky alternatives to common prenatal testing for genetic disease (amniocentesis or chorionic villus sampling), which, if the diagnosis is unfavorable, can result in difficult decisions about whether to continue the pregnancy. In 2011, next-generation sequencing was used to simultaneously analyze carriers for more than 400 target genes associated with severe childhood recessive diseases,* helping to spur the availability of expanded carrier testing for disease-associated genetic defects. Earlier this year, several genetic and medical organizations issued a clarification to the genetic and clinical communities on the current state of the art of such carrier testing. Another more recent approach called preimplantation genetic screening was introduced to detect aneuploidy (abnormal chromosome number) in IVF embryos derived from genetically normal parents. Both preimplantation genetic diagnosis and screening advanced through techniques that now allow longer in vitro cultivation of embryos (thereby providing more cells for analysis) and that detect gene copy number across all chromosomes using advanced molecular cytogenetics (comparative genomic hybridization on a DNA chip).

What about the possibility of detecting de novo mutations in preimplantation IVF embryos? An estimated 500 genes may undergo de novo mutations in every human embryo, leading to severe conditions in up to 0.5% of all pregnancies. But these mutations arise in the fetus, so expanded carrier testing will not identify couples at risk. However, screening IVF embryos for de novo mutations across the genome at high resolution is now theoretically possible with next-generation sequencing. For example, this technique could be applied to DNA from one to a few cultivated IVF embryonic cells, similar to the prenatal analysis of fetal DNA in the mother's plasma to detect aneuploidy. This deep sequencing requires unbiased whole-genome amplification starting with one or a few embryonic cells, and multiple efforts are being made to achieve this.

Through a combination of expanded carrier testing and preimplantation genetic diagnosis for inherited mutations, and preimplantation genetic screening with next-generation sequencing of most or all of the genome, it should be possible to prevent the occurrence of a great majority of both inherited and de novo single-gene disorders in children conceived through IVF. Furthermore, if new technologies allow the recovery of a few fetal cells from the mother's circulation during the first trimester of pregnancy, these diagnostics could theoretically detect severe deleterious genetic variations and mutations for all pregnancies and allow parents to consider the termination of pregnancy. As these sophisticated diagnostics evolve, raising difficult choices for some parents, society is likely to debate their use, interpretation of results, and costs. It is critical that the biomedical and scientific communities continue to engage with each other and with the public to ensure that the future vision of using next-generation sequencing in diagnostics remains clear.

  • * C. J. Bell et al., Sci. Transl. Med. 3, 65ra4 (2011).

  • J. G. Edwards et al., Obstet. Gynecol. 125, 653 (2015).

  • J. de Ligt et al., Curr. Opin. Genet. Dev. 23, 257 (2013).

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