Nonmosaic balanced homologous translocations of major clinical significance: Some may be mosaic

Abstract

The main mechanism proposed for formation of homologous translocations/isochromosomes is mitotic and if this occurs in a chromosomally normal conceptus, mosaicism would be expected to be seen. The lack of mosaicism in published cases of rearrangement (REA) of mitotic origin might be explained by under-detection due to the low level mosaicism for a normal line. Recently it was reported that sex-specific centromere instability in early embryogenesis leads to a female prevalence among individuals with mosaicism for pericentromeric rearrangements. To determine whether carriers of apparent non-mosaic homologous REA could be mosaics for a normal cell line, the sex ratio (male to female ratio) among carriers of balanced and unbalanced homologous translocations/isochromosomes was studied. This ratio was determined to establish if there is a female predominance similar to that seen in carriers of REA with mosaicism. In reviewing the literature, a female prevalence among fetuses with balanced homologous REA and among carriers of unbalanced homologous REA detected prenatally, postnatally and in miscarriages was found. Overall, there were 48 males and 72 females in the collected sample, and this ratio differed significantly from the expected sex ratio of 1.06 (P = 0.0075). There is not a male prevalence among miscarried fetuses, there is no evidence of selection against males in the collected material of this study. The analysis of sex ratios in different variants of trisomy 13 with respect to ascertainment (prenatal diagnosis, miscarriages, liveborn) also does not support an intrauterine selection against males as a cause of a female prevalence among carriers of homologous REA. Thus the data presented in this paper suggests that a proportion of the carriers of balanced homologous REA may have mosaicism for a normal line. Since low level mosaicism for a normal line in a translocation carrier would alter his/her reproductive options, it can be recommended that molecular polymorphic analysis be applied to these cases. This would allow those resulting from meiotic formation to be distinguished from those resulting from postzygotic formation. This latter mechanism may indicate the presence of a mosaicism for a normal line, making further intensive karyotypic analysis advisable. However, additional studies of healthy carriers of homologous REA of chromosome 14 or 15 should not be done. (c) 2007 Wiley-Liss, Inc.

Normal sperm in a 2;2 homologous male translocation carrier

“…The main mechanism proposed for homologous acrocentric translocations origin is mitotic and when exceptionally present in a chromosomally normal conceptus, mosaicism is expected to be seen [12]. In theory, carriers of these rearrangements have no chance of having normal offspring as they only produce abnormal gametes, resulting in monosomic or trisomic zygotes for the translocated chromosome [5]. Genetic counseling for these patients should include assisted reproductive technologies with donor sperm or ovum.…”

“…Translocations between homologous chromosomes are extremely rare, the majority involving acrocentric chromosomes [6]. Unlike translocations between two non-homologous acrocentric chromosomes, these have no chance of having normal offspring as they only produce abnormal gametes [5,6]. However, it was recently described the presence of normal sperm in the ejaculate of a homologous Robertsonian translocation carrier [2].…”

Mosaicism for structural non-centromeric autosomal rearrangements in disease-defined carriers: sex differences in the rearrangements profile and maternal age distributions

“…According to Barber [3], individuals were considered phenotypically affected when any type of phenotypic anomaly was reported, even if the etiological role of the chromosome abnormality in the same individual was questionable. From the sample collected, we further excluded cases of Rea with both breakpoints localized at pericentromeric regions, because of the strong female preponderance among carriers of such mosaicism [4, 5]. Cases of familial instability were also excluded from the study.…”

Resolving Paradoxes of Robertsonian Translocations

“…The sex ratio in carriers of HT of chromosomes 13-15 and 21 is female biased, varying from 0.21 to 0.54, with the overall figure of 0.34 (22 M/64F) with 95% CI of 0.21-0.56. The predominance of female individuals among carriers of chromosome rearrangements of this type is explained by the sex-specific instability of pericentromeric regions [15,69]. In contrast, sex…”

“…This phenomenon was shown both for ROB [65,66] and for nonacrocentric chromosomes [67,68]. Another possibility was discussed as well, gonadal mosaicism in unbalanced HT (translocation trisomy), since gamete precursor cells with such a set of chromosomes are expected to produce 50% of daughter cells with normal karyotype [69].…”