Chromosomal instability in first trimester miscarriage: a common cause of pregnancy loss?

Abstract

Background: First trimester miscarriage without underlying medical conditions is most commonly caused by chromosomal abnormalities reported to occur in 50% or more of cases. These chromosomal changes in early losses include both numerical abnormalities and structural alterations that result in gain and/or loss of genetic information. Structural alterations are much less common than numerical changes. Jumping translocations (JTs) are considered extremely rare with only four cases previously reported.

Methods: We report 12 examples of chromosome instability seen in the fetal material of spontaneous first trimester miscarriages in a single study population.

Results: In these examples, we observed different cell lines with related chromosomal alterations. Some may be considered to be JT, where a single donor site was observed with different recipients. Others involved more than one site on the "donor" chromosome. One reported miscarriage involved multiple aneuploidy. All alterations resulted in partial trisomies and monosomies which predisposed the pregnancy to chromosomal imbalance and subsequent demise. Patient demographic data did not indicate possible causes of the errors observed.

Conclusions: This is the first report of such a large cohort and is believed to be the result of increased knowledge and depth of analysis in this area, rather than a representation of confounding factors in this population. It is therefore proposed that identifying these chromosomal changes must be incorporated into the system of testing within the clinical environment. We must also recognize that some routine laboratory techniques will fail to detect such genetic changes.

Keywords: Chromosomal instability (CIN); chromosomes; jumping translocations (JTs); miscarriage; structural alterations.

Figure 1

Conceptus 6: mos46,XX,del(5)(p15.1)[12]/46,XX,del(5)(p11.2)[6]. Mosaicism for two cell lines with different deletions of chromosome 5. One cell line exhibited a deletion of the terminal region of 5p with a breakpoint at 5p15.1. The deletion of 5p in the second cell line was much larger with a breakpoint at p11.2, therefore losing most of the short arm. Larger figure represents a full karyotype with the smaller deleted 5p. Note random loss of 14 in the karyotyped cell. Inset: a partial karyotype to demonstrate the different deletions observed in the sample.

Figure 2

Conceptus 9: mos46,XY,inv dup(4)(p16.3p14)[22]/46,XY,der(4)t(3;4)(p21.3;p16.3)[12]/46,XY[36]. Mosaicism for a normal male cell line and two different alterations to chromosome 4p. The larger abnormal clone exhibited an inverted duplication of approximately half the short arm. The smaller clone exhibited a derivative 4 from an unbalanced translocation of approximately half the short arm of chromosome 3 and the distal region of chromosome 4p. There were two normal copies of chromosome 3 in every cell in this clone. Larger figure: full karyotype of the larger abnormal clone. Inset: partial karyotype demonstrating a normal 4, the inverted duplicated 4p and the derivative 4 from the 3;4 translocation.