Prenatal Counseling

The fetuses studied by Le Caignec had at least three malformations—variously in the cardiovascular, urogenital, skeletal, digestive, and central nervous systems. But when the list of identified anomalies was assessed, most of those fetuses, if examined by high-resolution ultrasonography, would have had anomalies identified in only 2 systems; the 3rd involved system would have been detectable only on fetopsy.

Rickman and colleagues used a custom array that focused on prenatal and pediatric abnormalities to examine the sensitivity and specificity of array CGH for detecting common aneuploidies in amniotic fluid specimens. All but 1 of the 30 subjects’ unbalanced chromosome rearrangements could be detected by array CGH—in some cases, from a specimen of amniotic fluid as small as 1 cc.

In Rickman’s hands, as well as in the hands of others, triploidy could not be detected, however—a problem that has been addressed in newer array platforms. In an additional 30 cases, no false positives were noted.

Similar results were obtained by Sahoo and co-workers: In 98 prenatal specimens (obtained by CVS or amniocentesis), there was complete concordance between the results of karyotype analysis and array CGH studies. In most cases, specimens were obtained because of advanced maternal age; only 19% represented concern over a sonographic abnormality. This study population included 4 cases of trisomy 21 and 1 case of an unbalanced translocation.

Notably, among the 98 specimens, 30 were thought to be characterized by gain or loss of copy number of 1 or more clones. Because these copy number repeats are recognized as normal variants (based on analyses of normal populations), they were considered copy number polymorphisms (CNPs) and without clinical significance to the fetus.

In addition, 12 cases contained a copy number imbalance that had not been recognized among normal controls. In 9 of those cases, the same loss or gain was demonstrated in 1 parent. In 1 other case, the parents elected not to be studied and, in the 2 others, the array finding was not confirmed on further testing (although low-level mosaicism could not be excluded). Sahoo’s team emphasizes both the targeted specificity of their custom array for well-characterized disorders, the reference to normal population databases being constructed for CNPs, the use of at least 3 clones for each disease locus, and the necessity for parental specimens to appropriately counsel the family about the presence of CNPs.

The work of Rickman and Sahoo reveals the potential for applying array CGH to a small volume of amniotic fluid or a specimen from direct CVS—a process that begins with whole-genome amplification. As this approach is refined to decrease the sample size and shorten the time to results even more, we can expect to see array CGH applied to areas where analysis has been constrained by the fact of small specimen size—such as preimplantation genetic screening.

Analysis of fetal loss will mean better counseling about recurrence

Fritz B, Hallerman C, Olert J, et al. Cytogenetic analyses of culture failures by comparative genomic hybridization (CGH)—re-evaluation of chromosome aberration rates in early spontaneous abortions. Eur J Hum Genet. 2001;9:539–547.

Schaeffer A, Chung J, Heretis K, et al. Comparative genomic hybridization-array analysis enhances the detection of aneuploidy and submicroscopic imbalances in spontaneous miscarriages. Am J Hum Genet. 2004;74:1168–1174.

Approximately 50% of 1st-trimester pregnancy losses are considered to be the results of chromosomal abnormalities. Often, however, it isn’t productive to analyze the products of conception because fetal cells fail to grow in culture or are overgrown by maternal cells. And, although chromosomal abnormalities play less of a role in 2nd-trimester fetal loss or in stillbirth, the rate of nondiagnostic results from classical cytogenetic study in such cases is high.

Sampling of the placenta or amniocentesis at the time fetal loss/stillbirth is recognized can lower the no-growth rate, but these methods have not been incorporated into practice universally. With array CGH, however, results can be obtained from uncultured cells, and that capability offers the opportunity to assess a demised fetus for common aneuplodies.

Array CGH will also provide an assessment of genomic imbalances that aren’t otherwise detectable at the resolution of metaphase chromosomes. Identification of a genomic imbalance—during a 1st- or 2nd-trimester loss—would facilitate an appropriate workup and lead to more accurate counseling about the risk of recurrence.

Assessment of nondividing cells reveals an unexpectedly high rate of chromosomal abnormality

Fritz and co-workers used array CGH to assess 60 cases of 1st-trimester spontaneous loss in which culture did not yield a karyotype result. Utilizing the older methodology of genomic CGH (ie, resolution is comparable to that of karyotype analysis), 72% of fetuses were found to have an underlying chromosome abnormality.