Product of Conception: Comprehensive Molecular Chromosome Screening

Chromosomal causes of miscarriages

Chromosomal aneuploidies (abnormal number of chromosomes) are the most common cause of first trimester miscarriage, accounting for more than 50% of spontaneous abortions¹.  Aneuploidies observed in products of conception (POCs) involve almost every chromosome (Figure 1), with trisomies being the most common chromosomal abnormality¹.

Technologies for genetic testing of POCs

Molecular cytogenetic techniques using array comparative genomic hybridisation (aCGH) or next generation sequencing (NGS), overcome limitations of other technologies by offering comprehensive chromosome screening (screening chromosomes 1-22, X&Y) and do not require cell culturing (as for traditional karyotyping), therefore mitigating test failures and ensuring the highest chance of obtaining meaningful results from POC specimens.  Although certain aneuploidies (such as trisomy 16) are more commonly found in early miscarriages, any of the chromosomes can be involved in an aneuploidy event and will be detected with comprehensive testing, as opposed to lab techniques that only detect specific chromosomes (FISH and QF-PCR).

The value of testing POCs

There is value in testing POC samples following an early pregnancy loss considering the high incidence of chromosomal abnormalities causing miscarriage.  The majority of miscarriages occur as a result of sporadic chromosomal abnormalities with a low risk of recurrence; however, this risk remains associated with maternal age³.  Some forms of chromosomal abnormalities (such as chromosomal translocations) are rare, but have a high risk of recurrence.  In these cases parental karyotyping will be needed to exclude a balanced translocation in a parent.  Any partial/segmental chromosomal abnormalities or recurring aneuploidies should be discussed with a genetic professional. By identifying the 50% of women whose pregnancy loss was due to chromosomal abnormalities, comprehensive chromosome screening can prevent a large proportion of patients undertaking further unnecessary and costly evaluations into the aetiology of the pregnancy loss.  Furthermore, the psychological benefit of identifying the aetiology of a foetal loss cannot be understated⁴.  Conversely, if a foetal chromosomal abnormality is excluded, there may be a possible treatable physiological cause for a given miscarriage and investigations can be focussed on identifying this.  Identifying or excluding a chromosome abnormality can therefore be used to guide counselling for future pregnancies.

PathCare Namibia offers POC chromosome analysis via two referral routes; both make use of a NGS test platform.  Both of these test options are indicated on the PathCare Namibia placenta and prenatal forms:

Products of Conception: comprehensive chromosome screen (Next Genetics):

• All aneuploidies will be detected
• Partial/segmental chromosome imbalances (≥10Mb) will be detected
• Certain triploidies and polyploidies will NOT be detected (e.g. 69, XXX)
• Balanced translocations will not be detected

Products of Conception: maternal cell contamination testing (first step) AND comprehensive chromosome screen (Unistel)

• All aneuploidies will be detected
• Partial/segmental chromosome imbalances (≥10Mb) will be detected
• All triploidies and polyploidies will be detected
• Maternal cell contamination studies are performed as a first step.  As some studies show maternal cell contamination rates of 22%, this is an important factor to consider¹
• Balanced translocations will not be detected

Please contact our genetics team at geneticconsult@pathcare.org or 021 596 3655 to discuss genetic testing strategies or the interpretation of genetic testing reports.

References

1. PMID 25004334: Levy et al. (2014) Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analysis.  Obstet Gynecol. 2014 Aug;124(2 Pt 1):202-9.
2. Shen et al. (2016) Molecular cytogenetics. 9:7
3. RCOG https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg17/
4. Sahoo et al. (2017) Genetics in Medicine. 19(1):83-89

Compiled by: Frieda Loubser, Maureen Conradie and Maxine du Toit