Objective
To compare the indications for invasive prenatal testing resulting in the detection of translocation Down syndrome and complete trisomy 21.
Study Design
This case control study was based on a large amniocentesis and chorionic villi samples database (n = 534,795). All specimens with translocation Down syndrome (n = 203) comprised the translocation group and were compared with a maternal age-matched group (4 to 1, n = 812) in which complete trisomy 21 was detected. Women with a normal karyotype were randomly selected (n = 812) and served as controls. Indications for invasive testing were compared among the 3 paired groups using χ 2 analysis.
Results
There were no differences in the incidence of abnormal first- and second-trimester screening tests between the translocation Down syndrome and the complete trisomy 21 groups. History of prior aneuploidy was significantly more frequent in the translocation Down syndrome group, as compared with either complete trisomy 21 fetuses or normal controls.
Conclusion
Fetuses with translocation Down syndrome present with the same screening abnormalities as fetuses with complete trisomy 21.
Down syndrome (DS) is a major cause of mental retardation, affecting 1 in 800 newborns. Approximately 95% of DS cases are caused by the presence of 3 copies of chromosome 21 (complete T21). This is most frequently the result of a maternal meiotic nondisjunction of the chromosome 21 pair. Less common forms of genetic aberrations that account for the remainder of DS cases include mosaicism of trisomy 21 and translocations involving chromosome 21. Each of these aberrations is thought to account for approximately 1-3% of all DS cases.
Extensive research in prenatal screening for DS has led to major advancements in our ability to identify affected fetuses during the first and second trimesters. These first- and second-trimester screening modalities use maternal serum analytes and fetal sonographic evaluation to modify the a priori, age-related risk for DS, and provide an individual, patient-specific risk assessment. Several protocols for combining these screening tests are now available (known as sequential, integrated, or contingent testing) and have been shown to significantly improve the detection rate of DS (>90%), whereas, decreasing the screen positive rate to approximately 3%.
Sonographic evaluation of the fetus in the second trimester can detect both major anomalies as well as characteristic soft markers associated with DS. This “genetic ultrasound” has been associated with a detection rate of 50-70% of DS fetuses. It is, however, also associated with a substantial screen positive rate.
Whereas an increase in maternal age is directly associated with an increased risk of complete T21, there is no such association in cases of translocations leading to DS (Trans-DS). Approximately 25% of unbalanced Robertsonian translocations that result in DS are inherited from a translocation carrier parent, and are therefore associated with a high recurrence rate.
The extensive research that has been dedicated to DS screening has focused primarily on the detection of fetuses with a complete T21 karyotype. A paucity of data exist regarding the prenatal detection of the less common forms of DS. Recently, we demonstrated that fetuses with mosaicism of trisomy 21 do not present with the same abnormal screening tests as fetuses with complete T21. However, data regarding the prenatal detection of fetuses with Trans-DS are still lacking. Therefore, the objective of our study was to analyze the indications for invasive prenatal testing leading to the detection of fetuses with Trans-DS and compare them with those of complete T21 and chromosomally normal fetuses.
Materials and Methods
We conducted a retrospective case control study to compare the major indications leading to the diagnosis of Trans-DS, complete T21, and normal fetuses. A large database (n = 534,795), including all of the amniocentesis and chorionic villi samples (CVS) processed by Genzyme Genetics (Philadelphia, PA) between February 2000 and December 2006, was available for this query. All these specimens had a clear indication documented for testing. If no indication was initially provided, the referring providers were contacted to ensure that the reason for the testing was known. All specimens identified with a translocation involving chromosome 21 (n = 203) comprised the Trans-DS group. If a translocation involved other chromosomes (not chromosome 21), it was excluded from this study. Subsequently, a maternal age-matched group of fetuses in which a complete T21 karyotype was detected were randomly selected from the total of 7355 T21 cases and comprised the complete T21 group (4 to 1 matching, n = 812). Specimens in which a normal karyotype was found were randomly selected (4 to 1 matching, n = 812) and served as the normal control group. Comparisons of the primary indications for invasive testing were performed among all 3 groups. These indications included history of a prior fetus or child with DS, an abnormal first-trimester screen (Ab1st), an abnormal second-trimester maternal serum screen (Ab2nd), abnormal second-trimester sonographic findings (AbUS), or a cystic hygroma. In addition, a separate analysis was performed on a subgroup of patients who had an isolated cardiac anomaly detected during the second-trimester scan.
We use χ 2 analysis to compare the 3 paired groups as to their population ethnicity as well as the distribution of the different types of invasive testing (CVS or amniocentesis) that were performed. The differences in the prevalence of each indication leading to invasive testing between each of the paired groups (Trans-DS to T21, Trans-DS to normal controls, and T21 to normal controls) were tested separately using χ 2 analysis. The effect of multiple comparisons was accounted for.
An “exempt review” status was obtained from the institutional review board as the review of an anonymous database does not qualify as human subject research.
Results
Our database was comprised of 534,795 samples, including 494,163 amniocentesis and 40,632 CVS samples. Of those, 203 cases met the inclusion criteria for Trans-DS. These included 100 cases of 14;21 translocations, 62 cases of 21;21 translocations, 16 cases of 13;21 translocations, 9 cases of 15;21 translocations, and 3 cases of 20;21 translocations. The remainder of the translocation cases (6.4% of the Trans-DS group) included rare translocations such as 1;21, 2;21, 4;21, 6;21, 7;21, 11;21, and 22;21.
Maternal ethnicity was distributed in a similar fashion among the 3 groups ( P = .69), and is displayed in Table 1 . There were no statistically significant differences in the distribution of cases diagnosed by amniocentesis or CVS among the 3 groups ( P = .76). This summary is presented in Table 2 .
| Ethnicity | Trans-DS | T21 | Normal |
|---|---|---|---|
| White | 80 (39.4%) | 290 (35.7%) | 283 (34.9%) |
| Hispanics | 33 (16.3%) | 136 (16.7%) | 140 (17.2%) |
| Asian | 18 (8.9%) | 84 (10.3%) | 101 (12.4%) |
| African American | 15 (7.4%) | 55 (6.8%) | 58 (7.1%) |
| Other | 17 (8.4%) | 90 (11.1%) | 68 (8.4%) |
| Unknown | 40 (19.7%) | 157 (19.3%) | 162 (20.0%) |
| Procedure | Trans-DS | T21 | Normal |
|---|---|---|---|
| Amniocentesis | 184 (90.6%) | 746 (91.9%) | 749 (92.2%) |
| CVS | 19 (9.4%) | 66 (8.1%) | 63 (7.8%) |
| Total | 203 (100%) | 812 (100%) | 812 (100%) |
A summary of the primary indications for invasive testing leading to the detection of Trans-DS, complete-T21, and normal karyotype fetuses is presented in Table 3 . History of a prior DS fetus or child was significantly more frequent in the Trans-DS group, as compared with both fetuses with T21 or with a normal karyotype. In contrast, there were no differences in the prevalence of the indications for invasive fetal testing (Ab1st, Ab2nd, AbUS, cystic hygroma, and cardiac anomalies) between the fetuses with Trans-DS and those with complete T21. As expected, the prevalence of Ab1st, Ab2nd, and AbUS was significantly higher in both the Trans-DS and T21 groups, as compared with normal controls.
| Variable | Trans-DS | T21 | Normal | Trans-DS vs T21 | Trans-DS vs normal | T21 vs normal |
|---|---|---|---|---|---|---|
| n | 203 | 812 | 812 | |||
| Maternal age (y ± SD) | 31.4 ± 6.7 | 31.5 ± 6.9 | 35.2 ± 5.5 | ns | < 0.001 | < 0.001 |
| History of aneuploidy | 21 (10.3%) | 30 (3.7%) | 25 (3.1%) | < 0.001 | < 0.001 | ns |
| Ab1st | 16 (7.9%) | 98 (12.1%) | 10 (1.2%) | ns | < 0.001 | < 0.001 |
| Ab2nd | 91 (44.8%) | 380 (46.8%) | 221 (27.2%) | ns | < 0.001 | < 0.001 |
| AbUS | 91 (44.8%) | 371 (45.7%) | 107 (13.2%) | ns | < 0.001 | < 0.001 |
| Cystic hygroma | 11 (5.4%) | 60 (7.4%) | 2 (0.003%) | ns | < 0.001 | < 0.001 |
| Cardiac anomaly | 20 (9.9%) | 72 (8.9%) | 10 (1.2%) | ns | < 0.001 | < 0.001 |
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