Reproductive risks for carriers of complex chromosome rearrangements: Analysis of 25 families

Abstract

We have determined the empirical reproductive risks for heterozygous carriers of complex chromosome rearrangements (CCRs). CCRs are structural rearrangements involving at least three chromosomes and three or more chromosomal breakpoints. Pregnancy outcome, the frequency and type of chromosomal imbalance in the offspring, and the localization and distribution of chromosome breakpoints were analyzed in 25 CCR families ascertained by the birth of a malformed child or repeated spontaneous abortions. This study included two newly ascertained familial CCRs and a total of 67 informative pregnancies. Analysis of the data, after correction for ascertainment bias, showed that the incidence of spontaneous abortions in CCR families was 48.3%. Approximately one in ten pregnancies and 18.4% of all live births to CCR carriers resulted in phenotypically abnormal offspring. One-half of all CCR carrier liveborn offspring were also CCR carriers. There was a 53.7% incidence of an abnormal pregnancy outcome to CCR carriers. We failed to detect any evidence for a non-random involvement of specific chromosomes in CCRs. However, we did observe a non-random distribution of specific breakpoints at sites 1q25, 4q13, 6q27, 7p14, 9q12, 11p11, 11p15, 12q21, 13q31, and 18q21.

Meiotic outcomes of three-way translocations ascertained in cleavage-stage embryos: refinement of reproductive risks and implications for PGD

“…A 20% risk of live-born offspring with an unbalanced translocation and an up to 50% risk of miscarriage have been recommended as appropriate general risk figures, 21 which is largely based on the obstetric history of female heterozygotes. 4,29 Due to spermatocyte arrest, very few male three-way translocation heterozygotes are likely to conceive without assisted conception; due to small numbers caution is advised but accepting a higher incidence of 3:3 alternate products, it could be appropriate to consider a lower general risk figure of around 3% (probably between 1 and 8%, Supplementary Appendix VIII) for live birth with chromosome imbalance. However, we suggest that a risk specific for each translocation, estimated using the method we have outlined (Supplementary Appendix III), is more useful in helping a couple decide whether PGD is preferable to natural pregnancy and prenatal diagnosis.…”

“…Out of 29 Table 4 shows that out of 29 embryos 8 (27.6%) were consistent with 3:3 alternate segregation resulting in a normal or balanced CCR chromosome complement. Twelve (41.4%) unbalanced embryos were consistent with 3:3 adjacent segregation of the translocations, of which two (6.9%) reflected adjacent-1 and 10 (34.5%) adjacent-2 segregation.…”

Constitutional complex chromosomal rearrangements in a klinefelter patient: case report and review of literature

“…In a study done by Gorski et al (1988) 25 families with CCRs had in total 67 pregnancies. The spontaneous abortions were 48.3% and 18.4% of the live born babies had malformation 16 [6].…”

“…2 The karyotype [(46,XX,t(1;3;5)(p22;q29;q22)] of the mother retardation and phenotypic abnormalities in de novo CCRs. However, CCRs can also be found in phenotypically normal individuals [2].…”

“…Balanced carriers of CCRs usually may have normal phenotype but often subfertility/infertility due to meiotic arrest and recurrent miscarriages in females are the main reasons for the detection of balanced CCRs [2].…”