Under‐ascertainment of mosaic carriers of balanced homologous acrocentric translocations and isochromosomes

Kovaleva, N. V.; Shaffer, Lisa G.

doi:10.1002/ajmg.a.20156

Cited by 23 publications

(22 citation statements)

References 63 publications

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“…In a recent study, however, only one male was found among 10 carriers of mosaicism for homologous translocations or isochromosomes [Kovaleva and Shaffer, 2003]. There are not enough data on mosaic carriers of other types of structural anomalies because of the rarity of such cases.…”

Section: Introductionmentioning

confidence: 97%

Sex-specific chromosome instability in early human development

Kovaleva

2005

Am. J. Med. Genet.

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The predominance of females segregating chromosome aberrations to their offspring has been explained mostly by selection disadvantage of unbalanced products of spermatogenesis. However, analysis of data from the literature supports the idea that somatic cells of early female embryos are similar to female germ cells in that they are prone to malsegregation. The goal of this study was to compare the sex ratio (male to female ratio) of carriers of presumably mitotic-occurring chromosome abnormalities to identify any sex biases. In examining the literature, we found a female prevalence in cases of mosaicism associated with uniparental disomy (UPD) (26 male individuals/conceptions and 45 female individuals/conceptions, sex ratio is 0.58, significantly different from 1.06 in newborn population, P = 0.0292). This predominance was highest at gestational age <16 week (8 male and 22 female conceptuses, sex ratio is 0.36, significantly different from expected figure of 1.28, P = 0.0025), which diminished at later stages of fetal development indicating potential correction of trisomies predominantly in females. There is a threefold prevalence of 46,XX/45,X mosaics over 46,XY/45,X mosaics in prenatally diagnosed cases, which also suggests a gender-specific postzygotic chromosome loss. The male prevalence in Prader-Willi syndrome with maternal UPD of chromosome 15 also can be explained by sex-specific trisomy correction, with predominant loss of a maternal chromosome causing biparental inheritance and therefore, complete correction of trisomy in females (without UPD). Finally, there is a female predominance in carriers of chromosome rearrangement with pericentromere break (mosaicism for Robertsonian translocation/isochromosome, centric fission, nonacrocentric isochromosome, and whole arm rearrangement), in both prenatal (21 males and 36 females, sex ratio is 0.58, P < 0.0184) and postnatal ill-defined cases (14 males and 35 females, sex ratio is 0.40, P = 0.001). Thus, the findings presented in this paper suggest that, in addition to reduction in male fertility, and to probable selection against abnormal cell line(s), there are two mechanisms that contribute to female preponderance among carriers of mosaicism: sex-specific chromosome loss and sex-specific centromere instability. The data obtained suggest that females may have gonadal mosaicism for aneuploidies and structural rearrangements more often than males. This may lead to the maternal origin bias in offspring with trisomies or structural rearrangements.

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Section: Introductionmentioning

confidence: 97%

Sex-specific chromosome instability in early human development

Kovaleva

2005

Am. J. Med. Genet.

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“…These second pool of normal spermatogonia would be in the origin of the 15.8 % normal sperm for chromosome 2 analyzed divisions after fertilization. As previously described [6], the presence of mosaicism for a normal cell line should be expected unless the rearrangement occur in the first zygotic cleavage where the chromatin is more unstable and more prone to rearrangements. In the present case, no normal cell line was found on lymphocytes and so, theoretically, no normal gametes and a successful pregnancy are expected.…”

Section: Discussionmentioning

confidence: 85%

“…In the present case, no normal cell line was found on lymphocytes and so, theoretically, no normal gametes and a successful pregnancy are expected. Even so, cryptic mosaicism is not possible to discard when analyzing only lymphocytes [6]. Mosaicism in other tissues is a hypothesis to be considered.…”

Section: Discussionmentioning

confidence: 99%

“…Translocations usually occur between two non-homologous chromosomes. 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].…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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Normal sperm in a 2;2 homologous male translocation carrier

Almeida

Dória

Moreira

et al. 2012

J Assist Reprod Genet

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Purpose Carriers of balanced structural chromosomal abnormalities are phenotypically normal but are at high risk of infertility. Translocations usually occur between two nonhomologous chromosomes. When occur between homologous chromosomes, an extremely rare event, generally involve acrocentric chromosomes. We present an infertile male referred for genetic analysis with a pure balanced homologous 2;2 translocation and normal sperm in the ejaculate. Methods Conventional cytogenetic and fluorescence in situ hybridization (FISH) were used in karyotype and sperm analysis, respectively. Results Male's karyotype revealed a pure balanced translocation involving homologous chromosomes 2: 46,XY,t(2;2) (p23;q21.2). Sperm analysis by FISH revealed the presence of 15.8 % of normal and 84.2 % of abnormal spermatozoa for chromosome 2. Conclusions This is the first report of confined gonadal mosaicism in a pure homologous non-acrocentric chromosome translocation carrier. Preimplantation genetic diagnosis for chromosome 2 should be offered as a reproductive option.

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

Kovaleva¹

2007

American J of Med Genetics Pt A

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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.

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Under‐ascertainment of mosaic carriers of balanced homologous acrocentric translocations and isochromosomes

Cited by 23 publications

References 63 publications

Sex-specific chromosome instability in early human development

Sex-specific chromosome instability in early human development

Normal sperm in a 2;2 homologous male translocation carrier

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

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