Mosaicism

 Mosaicism refers to the presence of two or more cell lines in an individual or tissue sample. Because invasive prenatal techniques, particularly CVS, sample extraembryonic tissues of the placenta, and not the fetus itself, mosaicism found in cultured fetal cells may be difficult to interpret. The prenatal geneticist must determine if the fetus is truly mosaic and understand the clinical significance of any apparent mosaicism.

Cytogeneticists distinguish three levels of mosaicism in amniotic fluid or CVS cell cultures based on the number of cells with mosaicism and the number of colonies from which they arise. Mosaicism detected in multiple colonies from several different primary cultures is considered true mosaicism. Postnatal studies have confirmed that true mosaicism in culture is associated with a high risk that mosaicism is present in the fetus. The probability varies with different situations. However, mosaicism for structural aberrations of chromosomes, for example, is hardly ever confirmed. Mosaicism involving several cells or colonies of cells from a single primary culture is difficult to interpret, but it is generally thought to reflect pseudomosaicism that has arisen in culture. When mosaicism is restricted to only a single cell, it is also considered to reflect pseudomosaicism and is typically disregarded.

Maternal cell contamination (MCC) can explain some cases of apparent mosaicism in which both XX and XY cell lines are present. This is more common in products of conception from miscarriages and in long- term CVS cultures than in amniotic fluid cell cultures because chorionic villi and maternal tissue are anatomically closely associated (see Fig. 1).

Fig1. Prenatal diagnostic procedures. (A) Amniocentesis. A needle is inserted transabdominally into the amniotic cavity, and a sample of amniotic fluid (usually ~20 mL) is withdrawn by syringe for diagnostic studies (e.g., chromosome studies, enzyme measurements, or DNA analysis). Ultrasonography is routinely performed before or during the procedure. (B) Chorionic villus sampling. Two alternative approaches are drawn: transcervical (by means of a flexible cannula) and transabdominal (with a spinal needle). In both approaches, success and safety depend on use of ultrasound imaging.

In CVS studies, mosaic discrepancies between the karyotypes found in the cytotrophoblast, villous stroma, and fetus have been reported in 1% to 2% of pregnancies studied at 10 to 11 weeks of gestation. Confined placental mosaicism (CPM) is mosaicism that is present in the placenta but not in the fetus (Fig. 2). CPM can be the result of a trisomic cell line arising postzygotically in the placenta, in which case the fetus will always be diploid. Another mechanism for CPM is trisomy res cue, where the zygote has trisomy, but postzygotically during one of the cell divisions one of the copies of the trisomic chromosome is lost, establishing diploid normal cell lineages, alongside the trisomic cells. Occasionally, a liveborn infant or fetus with non-mosaic trisomy 13 or trisomy 18 has been reported in a pregnancy with placental mosaicism for the trisomic cell line and a normal diploid cell line. It has been proposed that the placental diploid cell line improves the probability of intrauterine survival of a trisomic fetus. When trisomy rescue results in a diploid fetus, it raises the concern that the fetus could have retained two copies of a chromosome from the same parent, resulting in uniparental disomy (UPD). This can affect all chromosomes but is particularly concerning for chromosomes 7, 11, 14, or 15, which contain imprinted genes. For example, two maternal copies of chromosome 15 cause Prader- Willi syndrome, and two paternal copies are associated with Angelman syndrome. Thus when there is CPM for these chromosomes, tests should be done to exclude UPD.

Fig2. The different types of mosaicism that may be detected by prenatal diagnosis. (A) Generalized mosaicism with diploid (yellow) and abnormal aneuploid (blue) cell lineages affecting both the fetus and placenta. (B) Confined placental mosaicism with diploid and aneuploid cells in the placenta and a diploid fetus. (C) Mosaicism with only aneuploid cells in the placenta and a diploid fetus. (D) Mosaicism confined to the fetus with a diploid placenta. (Modified from Kalousek DK: Current topic: Confined placental mosaicism and intrauterine fetal development, Placenta 15:219– 230, 1994.)

Because CMA uses pooled DNA from tissues or cultured cells and does not examine individual cells the way karyotyping does, it is less sensitive for detection of mosaicism. Mosaicism in which 10% of the cells are aneuploid is difficult to detect as a copy number change by CMA, whereas 10% mosaicism will be detected with greater than 99% probability when 50 cells are examined by karyotype. CMA is even less sensitive for detecting mosaicism for a CNV of only a segment of a chromosome unless it is present in more than 20% to 25% of the cells.

Confirmation and interpretation of apparent mosaicism are difficult challenges in genetic counseling for prenatal diagnosis when mosaicism is identified during an amniocentesis because clinical outcome information on the different types and extents of mosaicism can be limited. Further studies such as cordocentesis (fetal blood sampling) may provide some guidance, but the interpretation can remain uncertain. If mosaicism is identified at the time of CVS, parents can be reassured if follow- up amniocentesis results is normal and UPD is excluded (see earlier), particularly if the prenatal ultrasound demonstrates normal growth and no congenital anomalies are visualized. Parents should be counseled in advance of the possibility for mosaicism and that its interpretation could be uncertain. After birth, an effort should be made to verify any abnormal chromosome findings suspected on the basis of prenatal diagnosis. Confirmation of mosaicism, or lack thereof, may prove helpful with respect to medical management as well as for genetic counseling of the specific couple and other family members.

Culture Failure and Maternal Cell Contamination

Prenatal diagnosis is time sensitive, and culture failure, which is fortunately very rare, can be a concern. When a CVS culture fails to grow, there is time to repeat the chromosome study with amniocentesis. If an amniotic fluid cell culture fails, either repeated amniocentesis or cordocentesis could be offered, depending on fetal age. MCC is another potential risk of prenatal sampling. During cell culture, contaminating maternal cells could outgrow the fetal cells. MCC can be suspected when there are XX cell lines with a male pregnancy and is common in CVS cultures as a consequence of the inti mate association between chorionic villi and the maternal tissue (see Fig. 1). To minimize the risk for MCC, maternal decidua present in a CVS must be carefully dissected and removed, but this does not always eliminate every cell of maternal origin. A maternal blood sample can also be utilized to confirm or refute MCC through parallel genotyping of the DNA from the maternal and fetal sample with use of polymorphisms.

Unexpected Findings: Variants of Uncertain Significance, Incidental and Secondary Findings

On occasion, prenatal chromosome analysis performed primarily to rule out aneuploidy reveals some other unusual chromosome finding (e.g., a rare chromosomal rearrangement, a marker chromosome, and now more commonly a VUS on CMA or exome sequencing and genome sequencing).

Unbalanced or de novo structural rearrangements may cause serious fetal abnormalities. If a parent carries a balanced structural rearrangement (e.g., a balanced translocation) that is present in unbalanced form in the fetus (unbalanced translocation), the consequences for the fetus can be serious. If a fetus has a structural chromosomal rearrangement that is also present in one of the parents, it is more likely to be a benign change without untoward consequences, but there are exceptions to this. They include variable expressivity and involvement of a region of the genome that contains imprinted genes.

CMA has a higher chance of detecting VUS than a karyotype analysis, which is one reason why it has been more selectively used for pregnancies with fetal anomalies rather than as a first- line test. As experience and knowledge of CNV in the human genome improves, the medical relevance of an increasingly greater fraction of CNVs will become clearer. The incidence of VUS with CMA has dropped to levels close to what is seen with a karyotype, justifying replacing fetal karyotyping by CMA for nearly all indications.

Exome sequencing and genome sequencing remain tests for second- line evaluation of pregnancies with fetal anomalies for which a genetic etiology is not identified by CMA. They both have a higher chance for detecting VUS, which can be mitigated by limiting prenatal analysis to genes relevant for the sonographic phenotype or family history. When a VUS is identified, analysis of parental data from trio sequencing may help with interpretation.

Incidental findings of pathogenic or likely pathogenic variants that are unrelated to the fetal phenotype but may cause a different serious condition can occasionally be discovered in the sequence of the fetal or parental samples. It is recommended that significant incidental findings related to serious childhood disorders in the fetal sample are reported. However, the reporting of parental findings (e.g., a variant that increases the risk for late- onset conditions such as cancer) often involves the option for parents to opt out of obtaining parental results. Secondary findings are pathogenic and likely pathogenic variants in a list of genes curated by the ACMG to be associated with diseases for which the discovery of these variants could result in health care measures that benefit the individual. In general, patients should be given the option to opt out of receiving secondary findings.

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مواضيع ذات صلة

X-Linked Inheritance

Preconception Genetic Screening and Testing

Introduction to Cytogenetics and Genome Analysis

Methods to Detect Fetal Chromosomal Abnormalities

The Origin and Frequency of Different Types of Mutation

Noninvasive Prenatal Screening by Analysis of Cell- Free Fetal DNA

Screening for Down Syndrome and Other Aneuploidies

Screening for Neural Tube Defects

Genetic Alterations Associated with Acromegaly

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

The Role of Epigenetics in Cancer