Vol. 007
PGS – Embryonic Mosaicism & Clinical Management

PGS - Embryonic Mosaicism & Clinical Management - Article Summaries【Abstract】
Preimplantation genetic screening (PGS) testing platform has evolved through the years fromFISH to aCGH and recently to Next-Generation Sequencing (NGS). With the increased sensitivity of NGS
technology, chromosomal mosaicism in the biopsy samples of embryos is easier to be detected and thetrue chromosomal make-ups of the biopsy samples can be better reflected. However, this also presents
new clinical challenges in counseling and management of these PGS results and embryos.
Preimplantation Genetic Diagnosis International Society (PGDIS) previously released a position
statement discussing chromosome mosaicism in PGS testing. Sachdev et al. recently published a paper
regarding diagnosis and clinical management of embryonic mosaicism. Both provide resources forclinicians in handling these challenges.
Euploid embryos remain the top priority in selecting embryos for transfer. If another IVF cycle
to increase the chance of euploid embryos is not possible or wanted, transfer of embryos withchromosomal mosaicism may be considered after thorough counseling. Studies have suggested embryoswith chromosomal mosaicism may be associated with decreased potential for implantation andpregnancy development, and increased risks for fetal genetic abnormalities and adverse obstetricoutcomes. However, studies have also shown these embryos have potential to result in healthy babies.
Mosaicism involving trisomic or monosomic of any chromosome is associated with fetal and obstetricrisks. These authors suggest transfer of embryos with mosaic trisomies 2, 7, 13, 14, 15, 16, 18 and 21
may pose the most risks for adverse outcome. Prenatal genetic diagnosis through invasive procedures
remains the criterion standard for prenatal diagnosis of chromosomal abnormalities.

【Article #1 Excerpts】

Preimplantation Genetic Diagnosis International Society (PGDIS) released a position statement
regarding chromosome mosaicism and preimplantation aneuploidy testing in July of 2016. The following
are excerpts taken from the position statement, which is posted on PGDIS official website:
http://www.pgdis.org/docs/newsletter_071816.html.
Recommendations for the Clinician
1. Patients should continue to be advised that any genetic test based on sampling one or small
number of cells biopsied from preimplantation embryos cannot be 100% accurate for a
combination of technical and biological factors, including chromosome mosaicism.

GGA Corp. Genetic Counseling Newsletter – Vol. 007
PGS – Embryonic Mosaicism and Clinical Management

2.

2

The patient information and consent forms for aneuploidy testing (if used) should be modified toinclude the possibility of mosaic aneuploid results and any potential risks in the event of transferand implantation. This needs to be explained to patients by the clinician recommending theaneuploidy testing.
3. Transfer of blastocysts with a normal euploid result should always be prioritized over thosewith mosaic aneuploid results.
4. In the event of considering the transfer of a blastocyst with only mosaic aneuploidies, thefollowing options should be discussed with the patient:a. further cycle of IVF with aneuploidy testing to increase the chance of identifying a normal
euploid blastocyst for transfer
b. Transfer of a blastocyst with mosaic aneuploidies for low risk chromosomes only, afterappropriate genetic counseling if availablec. Appropriate monitoring and prenatal diagnosis of any resulting pregnancy, preferably by
early amniocentesis (> 14 weeks gestation).
Suggested Guidelines to Prioritize Mosaic Embryos for Transfer
Based on our current knowledge of the reproductive outcomes of fetal and placental mosaicism
from prenatal diagnosis, the following can be used as a guide by the clinician (or a genetic counselor ifavailable) when a mosaic embryo is being considered for transfer:
1. Embryos showing mosaic euploid/monosomy are preferable to euploid/trisomy, given thatmonosomic embryos (excepting 45, X) are not viable
2. If a decision is made to transfer mosaic embryos trisomic for a single chromosome, one canprioritize selection based on the level of mosaicism and the specific chromosome involveda. The preferable transfer category consists of mosaic embryos trisomic for chromosomes
1, 3, 4, 5, 6, 8, 9, 10, 11, 12, 17, 19, 20, 22, X, Y. None of these chromosomes involve theadverse characteristics enumerated below
b. Embryos mosaic for trisomies that are associated with potential for uniparental disomy(14, 15) are of lesser priority
c. Embryos mosaic for trisomies that are associated with intrauterine growth retardation(chromosomes 2, 7, 16) are of lesser priority
d. Embryos mosaic for trisomies capable of liveborn viability (chromosomes 13, 18, 21) areof lowest priority, for obvious reasons
Article reference:
Preimplantation Genetic Diagnosis International Society. PGDIS position statementonchromosome mosaicism and preimplantation aneuploidy testing at the blastocyst stage. PGDIS Newsletter, July 19,
2016. Available at: http://www.pgdis.org/docs/newsletter_071816.html. Accessed March 27, 2017.

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GGA Corp. Genetic Counseling Newsletter – Vol. 007
PGS – Embryonic Mosaicism and Clinical Management

3【Article #2 Summary Points】
Journal: Fertility and Sterility
Publication Date: 2017/1

Mechanisms Causing and Correcting Chromosomal Mosaicism
Embryonic chromosomal mosaicism describes the presence of two or more types of cells withdifferent chromosomal complements within the same embryo.
There are many mechanisms causing an originally diploid embryo to develop into a mosaic state,including “anaphase lag, mitotic nondisjunction, inadvertent chromosome demolition, or premature cell
division before DNA duplication”. Because of these reasons, chromosomal mosaicism is commonlydetected in cleavage-stage blastomere biopsies. One study has shown that nearly 50% of mosaic
cleavage-stage embryos were self-corrected to euploid blastocysts when left in extended culture.
Mechanisms for self-correction of chromosomal aneuploidies include “increased apoptosis ofaneuploidy cells, decreased division of aneuploidy cells in relation to euploid cells, preferential
development of euploid cells within the inner cell mass”, and trisomy rescue.
Detection of Mosaicism and Interpretation of Mosaic Results
Technical platforms for PGS testing has evolved through the years from FISH technology focusing on
selected chromosomes, to aCGH platform screening of entire chromosome set, and recently to NGS
technology with improved accuracies and lower costs. With its greater sensitivity, detection ofchromosomal mosaicism has been easier than before with this new NGS technology. This allows test
results to better reflect the true chromosomal make-ups of the biopsy samples. With the increased
reporting of chromosomal mosaicism, the issue of whether test results from a single trophectoderm
biopsy is indicative of the chromosomal complement of the entire embryo is again a popular discussion
topic.
Which Patient Population is at Risk for Mosaicism?
It is well known that advancing maternal age is associated with increased chances for aneuploidy.
However, whether maternal age is a factor leading to chromosomal mosaicism is less clear. Sachdev et al.
reviewed publications with maternal ages and PGS results, and suggested that there are no correlations
between advancing maternal ages and chances of chromosomal mosaicism.
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PGS – Embryonic Mosaicism and Clinical Management

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The authors suggest pre-test counseling regarding PGS testing should include: “a discussion about
the frequency of mosaic results, the challenges associated with interpretation of these results, thepossibility of a false positive diagnosis of embryonic mosaicism, and the limited predictive dataavailable”. A thorough pre-test counseling help the patients understand the risks/benefits/limitations of
PGS testing, and can therefore make an informed choice that is most suitable for their own needs.
Current knowledge supports preferential transfer of euploid embryos. However, sometimes there areno euploid embryos for selection. The authors suggest if there are no euploid embryos for consideration
and another IVF cycle to collect more embryos to increase the chance of euploid embryos is not possibleor wanted, then transfer of mosaic embryos can be considered after comprehensive counselingregarding possible obstetric and fetal risks.
Embryo Selection
Sachdev et al. referred to the position statement from PGDIS in discussing selection of mosaic
embryos for transfer – embryos with mosaic trisomies involving chromosomes # 1, 3, 4, 5, 6, 8, 9, 10, 11,12, 17, 19, 20, 22, X and Y, are preferred over those involving chromosomes # 2, 7, 13, 14, 15, 16, 18 and21.
Most of the time, an embryo with pure aneuploidy (non-mosaic, all cells carry aneuploidchromosomes) is non-viable. However, mosaicisms involving almost all chromosomes have beenreported to result in live-borns with clinical abnormalities. The clinical severity depends on theproportions and the distributions of abnormal cells. Therefore, there are still risks of fetal abnormalities
even with those chromosomes considered to be “safer” or “preferred” for transfer. Transfer of mosaic
embryos involving any chromosome should be handled with cautions, and thorough patient
counseling should be provided.
Prenatal Testing after Transfer of Mosaic Embryos
With the advancement in genetic testing technology, options of prenatal genetic testing haveexpanded. However, to date, genetic testing through invasive procedures, such as amniocentesis,
remains the gold standard for prenatal diagnosis of fetal chromosomal abnormalities.
Article reference: Sachdev NM, Maxwell SM, Besser AG, and Grifo JA. Diagnosis and clinical management of embryonicmosaicism. Fertil Steril. 2017 Jan;107(1):6-11. PubMed PMID: 27842993.

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