Boy with bilateral retinoblastoma due to an unusual ring chromosome 13 with activation of a latent centromere

Abstract

We present a patient with bilateral retinoblastoma and developmental delay who has an abnormal male karyotype containing 47 chromosomes, including an acentric derivative chromosome 13. We postulate that the derivative 13 occurred after a break at 13q14, with the proximal portion of the chromosome forming a ring and the distal portion undergoing duplication. Thus, this patient is trisomic for 13q14-->qter. The derivative chromosome with duplicated distal portion (13q14-->qter) lacked the 13 centromere and was negative for chromosome 13 alpha-satellite DNA by low stringency FISH. Nevertheless, this chromosome is stably transmitted in lymphocytes and fibroblasts. A single primary constriction was observed at band 13q21, consistent with activation of a latent centromere (neocentromere) at this band. The neocentromere on der(13) was positive for multiple centromeric proteins, suggesting that it acts as the functional centromere. By FISH, the Rb gene was present on the normal 13, the proximally derived ring chromosome, but not on the derivative chromosome. Although there was no evidence for disruption of the Rb gene, this chromosome rearrangement most likely results in abnormal expression of the Rb gene product.

Mosaic monosomy of a neocentric ring chromosome maps brachyphalangy and growth hormone deficiency to 13q31.1‐13q32.3

“…Neocentromeres 13a–h are as described by Warburton et al [2000]with additional fine mapping of cases 13b, 13d, and 13g by Alonso et al [2003]. Additional cases are 13i [Morrissette et al, 2001], 13j [Knegt et al, 2003], 13k‐m, which are cases BC, MG, and JM, respectively, as described by Li et al [2002], and 13n [Barwell et al, 2004]. 13o is the present case.…”

“…This is exemplified in general by the clustering of neocentromeres at regions on 3q, 9p, 13q, 15q and Yq, and specifically by the fact that 15 of the 73 human neocentromere sites (21%) described to date localise to 13q [Amor and Choo, 2002; Barbi et al, 2003; Knegt et al, 2003; Ventura et al, 2003, 2004; Warburton et al, 2003, 2004; Amor et al, 2004; Barwell et al, 2004]. Within 13q, a clustering of neocentromeres has been identified, with neocentromeres mapped to bands 13q21 (five cases), 13q31 (two cases), 13q32 (seven cases), and 13q31/32 (present case) [Warburton et al, 2000; Morrissette et al, 2001; Li et al, 2002; Knegt et al, 2003; Barwell et al, 2004]. Localization of three neocentromere sites at 13q32 has been performed at a higher resolution using CENP‐A chromatin immunoprecipitation (ChIP) and genomic microarray analysis, demonstrating that each of these neocentromeres occupies a distinct and non‐overlapping genomic location within 13q32 [Alonso et al, 2003].…”

Tetrasomy 13q31.1qter due to an inverted duplicated neocentric marker chromosome in a fetus with multiple malformations

“…In these neocentric sSMC 13q, four distinct regions have been found to contain neocentromeres: 13q21 (five cases) [Tohma et al, 1998; Morrissette et al, 2001; Li et al, 2002; Knegt et al, 2003; Dhar et al, 2009], 13q31 (five cases) [Tohma et al, 1998; Barwell et al, 2004; Tonnies et al, 2006; Liehr et al, 2007; Mascarenhas et al, 2008], 13q31/32 (one case) [Amor et al, 2005] and 13q32 (seven cases) [Depinet et al, 1997; Lozzio et al, 1997; Warburton et al, 1997; Govaerts et al, 1999; Rivera et al, 1999; Li et al, 2002] (Table I).…”

Neocentromeres and epigenetically inherited features of centromeres

“…Solid tumors in cases of well-differentiated liposarcomas are cytogenetically characterized by the presence of a supernumerary ring or giant chromosome with amplified material from the 12q14–21 region combined with DNA from other chromosomes and a neocentromere (Italiano et al, 2009). Other types of human cancers associated with neocentromeres include: retinoblastoma (Morrissette et al, 2001), non-Hodgkin’s lymphoma (Blom et al, 2010), acute myeloid leukemia (de Figueiredo et al, 2009), and lung cancer (Italiano et al, 2006). Interestingly, CENP-A is overexpressed in several types of cancer cells (Tomonaga et al, 2003, Amato et al, 2009) and high CENP-A expression correlated with shorter survival times in lung cancer patients (Wu et al, 2012).…”