3.1. Mosaic Trisomy Profile and Clinical Outcomes in Prenatal Diagnoses. Comparing Mosaic Trisomy Profile in Prenatal and Postnatal Diagnoses
From the 596 selected papers, we retrieved data on 1266 cases of mosaic trisomies for chromosomes 1–22 (mosT1–mosT22). Despite every effort to collect as many cases of mosaics for rare trisomy as possible, only a few cases involving chromosomes 1, 4, 11 and 19 were identified. TFM was diagnosed in 271 cases, CPM in 553 cases, Not confirmed in 130 cases, and PNM in 317 cases. The data are presented in
Table 1 and
Table 2.
In prenatal diagnoses, the involvement of different chromosomes in every studied category is disproportional, varying from 0 (mosT1 and mosT19) to 28 cases (mosT9) in the TFM cohort and to 64 (mosT7) and 65 (mosT16) cases in the CPM cohort. The rate of some chromosomes might be different between TFM and CPM, for example, 6% vs. 12% of mosT7 and 7% vs. 1% of mosT16, but no statistically significant difference was found. However, we should compare the chromosome involvement with caution, since the mode of the data collection in this study might not allow for completely unbiased samples.
Expectedly, in the CPM cohort, normal outcomes prevailed compared to abnormal. However, the most apparent differences between the TFM and CPM cohorts were not the overall proportion of normal (34% vs. 67%) and abnormal outcomes (52% vs. 13%) but the chromosome-specific relations between normal and abnormal outcomes. More abnormal than normal (including or not including IUGR) outcomes were reported for mosaic trisomies 2, 4, 5, 9, 14–18, and 22. In contrast, more normal (including or not including IUGR) than abnormal outcomes were reported for mosaic trisomies 7, 8, 12, 13, and 21. The prevalence of IUGR did not differ significantly, i.e., 10% vs. 15%, while the proportion of fetal losses was 5% in both. It should be noted that in these groups, TFM (generalized mosaicism) and CPM (mosaic placental and a fetus with an apparently normal chromosome set), the reasons for fetal loss were likely different.
The cohort of non-confirmed cases demonstrated an intermediate rate of abnormal outcomes, being a mixture of TFM and CPM cases. A higher rate of fetal losses is explained by the accumulation of cases not followed up because of various reasons, including a poor growth of cells from a product of conception. In this group, we see a higher number of mosaic trisomies 9 and 14 among abnormal outcomes, while all other mosaic trisomies prevail among normal outcomes, likely indicating a predominantly CPM origin.
Since no statistically significant difference among the TFM and CPM cohorts was observed, all three prenatal cohorts were pooled and compared with the postnatal cohort (
Table 2).
A comparison of the data collected from different sources should be performed with caution because of the highly probable publication bias in favor of most rare trisomies and underreporting of “less interesting” common mosaics. This may be the reason for the mosT14 prevalence over mosT21 in postnatal diagnoses (n = 27 vs. n = 40), in contrast to their numbers in prenatal diagnoses (n = 22 vs. n = 61). Nevertheless, it is remarkable that some mosaic trisomies found in appreciable numbers in prenatal diagnoses are exceptionally infrequent (mosT4 and mosT6) or absent (mosT5 and mosT11) in postnatal diagnoses. At the same time, among prenatally detected cases of the listed mosaic trisomies, there were 4, 13, 9, and 8 normal outcomes, which might explain their rarity among postnatal (mostly abnormal) diagnoses.
3.2. Maternal Age Distribution in Prenatal Diagnoses, Normal Outcomes vs. Abnormal
Since offspring with IUGR represents an appreciable part of outcomes, we performed a preliminary comparative study, which showed no difference in the proportion of mothers with advanced maternal ages (AMA, ≥35 yr) between normal pregnancy outcomes with appropriate birth weight (n = 234) and those with intrauterine growth restriction but otherwise normal (n = 48), 74% and 73%, correspondingly
Table 3).
Data on maternal age distributions are presented in
Table 4. No statistically significant difference was found between TFM and CPM in both cohorts, so they were pooled, and those cases that were not precisely identified as TFM or CPM due to termination of pregnancy or because of lack of information on follow-up were added. Overall, in contrast to reasonable expectation, mothers of normal offspring appeared to be older compared to those with abnormal pregnancy outcomes (average age of 35.8 yr vs. 33.9 yr). The proportions of AMA mothers were 73% vs. 56%, correspondingly,
p = 0.0015. One may suggest an enhanced selective miscarriage of abnormal pregnancies with advancing maternal age, as it was demonstrated for trisomy 21 pregnancies [
25], as well as for other trisomies [
26]. However, women with pregnancy loss were younger than mothers of normal offspring and slightly younger than those with abnormal outcomes, with an average age of 33.3 yr and 50% proportion of AMA.
p = 0.0011.
3.3. Maternal Age and Parental Origin of Diploid Cell Line
Recent observation of a higher proportion of older mothers in mosaic carriers with concomitant UPD(14) [
27] prompted us to verify this phenomenon on a larger sample of mosaic trisomies. We have identified cases with the largest numbers of known parental origin of diploid cell line and known maternal age. These were mosT7 (n = 14), mosT14 (n = 23), mosT15 (n = 24), and mosT16 (n = 34) (
Table 5).
In all these groups, a higher AMA proportion was found for carriers of concomitant UPD compared to carriers with BPD (72% vs. 58%, 92% vs. 55%, 87% vs. 78%, and 65% vs. 24%, correspondingly). Overall figures were 78% vs. 48%, p = 0.0026. These data cannot be explained by random unequal distribution into prenatal and postnatal cohorts since UPD and BPD cases appeared to be well balanced regarding their numbers and their sources.
This is a quite intriguing finding because of the common mechanism of both UPD and BPD formation, i.e., the correction of original trisomy by loss of an extra chromosome. If this phenomenon is confirmed in future studies, one may speculate on a special mechanism of preferential disposal of the chromosome inherited from the other parent, associated with advancing maternal age.
3.4. Maternal Reproductive History in Prenatal Diagnoses vs. Postnatally Diagnosed Mosaicism
Analysis of published cases revealed the absence or poor reporting of maternal reproductive history in the majority of them. Only 339 histories were available for the analysis (
Table 6).
Among them, four categories were informative: primigravidas, complicated histories, uncomplicated histories, and fetal loss. The category ‘other complications’ included histories of pregnancy termination with no reason indicated. Some of them may be pregnancy loss. There is the same problem with the category ‘inconclusive reports’, containing cases with a discrepancy between the number of pregnancies and the number of deliveries.
Nevertheless, the data collected allowed justifying the comparison and subsequent pooling of the TFM and CPM cohorts against postnatal cohort. The overall frequency of mothers having had previous fetal loss(es) in the prenatal cohort was 16% vs. 30% in the postnatal cohort,
p = 0.0072. Advancing maternal age is associated with enhancing miscarriage [
28,
29]. However, mothers from the prenatal cohort reporting previous miscarriage(s) and those with uncomplicated reproductive history did not differ by a proportion of AMA, 67% and 66%, respectively. In the postnatal cohort, corresponding figures were
2541
59% and
1630
47%; therefore, the expected difference was not statistically significant due to small samples.
In the ‘other complications’ cohort, there were 10 mothers of fetuses reported with various mosaic trisomies, having had a previous offspring with a different chromosomal abnormality, including eight cases with T21, which may be interpreted as a genetic predisposition to chromosome nondisjunction. In addition, there were four cases of trisomy 21 recurrence, suggestive of parental gonadal mosaicism. The occurrence of a previous chromosome abnormality in the prenatal cohort, seems to be extremely high, 1 in 13 (14/180 excluding 57 primigravidas) or
4.7.8.1
13.0%. As a history of chromosomal anomaly is one of the most common indications for prenatal testing, we compared this figure with published data on the occurrence of autosomal trisomies in prenatal testing for previous de novo chromosome abnormality. Among 2,623 diagnoses for this indication, there were 37 cases of abnormal fetus, i.e., 1 in 79 or
1.01.4
1.9% [
30]. Caron et al. reported a similar figure of 1 in 72 (17/1232) or
0.91.4
2.2%, while among 2490 diagnoses for AMA indication, previous occurrence of autosome trisomies was 1 in 102 (247/24,901) [
31]. Differences between the data from this study and published data are highly significant, with
p = 2
.× 10
−6 nd
p = 7 × 10
−6, correspondingly. The reason for this difference between mosaic and nonmosaic aneuploidies is unclear.
In the postnatal cohort, six cases were identified with proven or suggested parental gonadal mosaicism: a woman with hysteria and her daughter suffered from undiagnosed mental illness, both with mosT7 [
32]; a boy and his mother, both with mosT10 [
33]; a mother and her two daughters with mosT13 [
34]; a girl with mosT21 and her mother reported with three previous spontaneous abortions [
35]; two non-twin siblings with mosT18 [
36]; and two non-twin siblings with mosT21 [
37]. Among 98 postnatal cases with known maternal reproductive history, the occurrence of “transmitted” mosaicism was 1 in 16, which is very similar to the finding in the prenatal cohort.
The inheritance of chromosomal mosaicism is not uncommon; for example, mosT21 in successive generations was documented in 12 of 80 families of carriers of gonadal mosaicism [
38]. It was reported repeatedly that gonadal mosaicism may account for more cases than it detected cytogenetically in somatic tissue(s) [
39,
40,
41,
42]. At the same time, theoretically, a large proportion of carriers of gonadal mosaicism can be identified by analyzing the proband’s trisomic line for the presence of two homologues from the same grandparent [
43]. However, no subsequent reports on uncovering parental gonadal mosaicism using this approach were published.