Duplications in addition to terminal deletions are present in a proportion of ring chromosomes: clues to the mechanisms of formation

Abstract

Background and methods: Ring chromosomes are often associated with abnormal phenotypes because of loss of genomic material at one or both ends. In some cases no deletion has been detected and the abnormal phenotype has been attributed to mitotic ring instability. We investigated 33 different ring chromosomes in patients with phenotypic abnormalities by array based comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH).Results: In seven cases we found not only the expected terminal deletion but also a contiguous duplication. FISH analysis in some of these cases demonstrated that the duplication was inverted. Thus these ring chromosomes derived through a classical inv dup del rearrangement consisting of a deletion and an inverted duplication. Discussion: Inv dup del rearrangements have been reported for several chromosomes, but hardly ever in ring chromosomes. Our findings highlight a new mechanism for the formation of some ring chromosomes and show that inv dup del rearrangements may be stabilised not only through telomere healing and telomere capture but also through circularisation. This type of mechanism must be kept in mind when evaluating possible genotypephenotype correlations in ring chromosomes since in these cases: (1) the deletion may be larger or smaller than first estimated based on the size of the ring, with a different impact on the phenotype; and (2) the associated duplication will in general cause further phenotypic anomalies and might confuse the genotype-phenotype correlation. Moreover, these findings explain some phenotypic peculiarities which previously were attributed to a wide phenotypic variation or hidden mosaicism related to the instability of the ring.

The Human Cleavage Stage Embryo Is a Cradle of Chromosomal Rearrangements

“…Many non-recurrent inv dup del rearrangements, which result from an asymmetric breakage of a symmetric dicentric chromosome in a pre-meiotic, meiotic or postzygotic anaphase, have been detected during pre-and postnatal genetic diagnoses [Zuffardi et al, 2009]. Also, ring and translocation chromosomes have been found to contain inv dup scars at the fusion or the break point [Rossi et al, 2007]. Finally, centric fission has been characterized as an important driver of karyotype evolution [Perry et al, 2004] and i(p) and i(q) formation is an important mechanism in UPID etiology [Kotzot, 2001[Kotzot, , 2008.…”

Ring chromosome instability evaluation in six patients with autosomal rings

“…Alternatively, they can be formed by subtelomeric sequence fusion or telomere-telomere fusion with no loss of genetic material, resulting in complete ring chromosomes (Henegariu et al, 1997;Sigurdardottir et al, 1999;Vermeesch et al, 2002;Le Caigne et al, 2004). Based on high-resolution molecular karyotyping, other mechanisms of the formation of ring chromosomes have been proposed, such as rings originating from an inverted duplication with a terminal deletion rearrangement (Knijnenburg et al, 2007;Rossi et al, 2008a).…”

“…Thus, a cryptic deletion may be the basis of the phenotypic abnormalities in apparently complete rings, such as the deletion of the IGF1R gene at 15q26.3 in a ring 15. Also, the phenotypic variability seen in patients with similar ring chromosomes may be a consequence of their instability and of the variation in gene dosage of each cell (Hecht, 1969;Palmer et al, 1977;Zuffardi et al, 1980;Knijnenburg et al, 2007;Rossi et al, 2008a), as for instance in the patient with a ring 18 reported by Koç et al (2008) who showed partial trisomy 18 in a considerable number of cells, due to the formation of dicentric rings, which resulted in a more severe phenotype. Rossi et al (2008a) described a patient with a ring 13 who had a deletion and a duplication of approximately 6 Mb each, oligohydramnios and cystic kidney, features that were attributed to trisomy 13.…”

Inverted duplications deletions: underdiagnosed rearrangements??

“…2 in ref 53). Rossi et al (53) found that 7 out 33 ring chromosomes were in fact not only deleted but also duplicated indicating that a precise mechanism is operating. Here, again, the presence of an inv dup del chromosome, although in a circular form, led us to hypothesize that the starting point was a symmetric dicentric chromosome present in the zygote or in early embryogenesis.…”

“…Recently two papers (41,53) have been published describing ring chromosomes in which array-CGH analysis showed not only the expected deletion at one or both chromosome ends but also a contiguous duplication (Fig. 4).…”