A molecular genetic approach to the identification of isochromosomes of chromosome 21

Abstract

The largest class of de novo chromosomal rearrangements in Down syndrome are rea(21q21q). Classically, these rearrangements have been termed Robertsonian translocations, implying an attachment of two different chromosome 21 homologues. Additionally, a Robertsonian translocation between two chromosomes 21 cannot be distinguished from an isochromosome composed of genetically identical arms by cytogenetic analyses. Therefore, we have used molecular techniques to differentiate between true Robertsonian translocations and isochromosomes. Samples were obtained from 12 probands, ascertained for de novo rearrangements between homologous chromosomes 21 [11 rea(21q21q) and 1 rea (21;21)(q22;q22)], their parents (n = 24) and available siblings (n = 7). The parental origins of the de novo rearrangements were assigned using molecular and cytogenetic analyses. Although not statistically significant, there was a two-fold increase in the number of paternally derived de novo rearrangements (n = 8) as compared with maternally derived rearrangements (n = 4). To distinguish between rob(21q21q) and i(21q), we used restriction fragment length polymorphisms (RFLPs) spanning the length of chromosome 21. Using all informative and partially informative RFLPs, we used the method of maximum likelihood to assign the most likely rearrangement definition (i or rob) and parental origin in each family. The maximum likelihood estimates indicated that all rearrangements tested (n = 8) were isochromosomes. C-banding revealed two centromeres in three cases indicating that a U-type exchange occurred between sister chromatids in these rearrangements. Our results suggest that the majority of de novo rea(21q21q) are isochromosomes derived from a single parental chromosome 21.

Mosaic Trisomy 21/Monosomy 21 in a Living Female Infant

“…The presence of a 46,N cell line in mosaic cases implies that the isochromosome occurred at a later mitosis [for detailed review see Gardner and Sutherland, 2004]. Molecular studies suggest that isochromosomes 21 most commonly originate at early postzygotic mitosis [Antonarakis et al, 1990;Shaffer et al, 1991]. According to the classical theory, early postzygotic isochromosome formation by centromeric misdivision should result in a trisomic cell line for 21q and a complementary cell line with monosomy 21.…”

Dual-color fish analysis of breakpoints on robertsonian translocations

“…Most of the homologous Robertsonian translocations so far reported have been monocentric (Wolff and Schwartz, 1992) and isochromosomes (Grasso et aL, 1989;Antonarakis et al, 1990;Shaffer et al, 1991). Of the two cases of homol- Vol.…”

Prenatal Diagnosis of Translocation 13;13 Patau Syndrome: Clinical Features of Two Cases

“…On the cytogenetic level, it was not possible to distinguish an isochromosome i(13q) from a Robertsonian translocation of two homologous chromosomes 13. DNA studies of trisomy 21 due to de novo rea(21q;21q) have concluded that the majority is due to isochromosomes i(21q) and not translocations between two chromosomes 21 [14][15][16][17]. Similar [18][19][20][21].…”