Chromosome 13q neocentromeres: Molecular cytogenetic characterization of three additional cases and clinical spectrum

Abstract

We report three new cases of chromosome 13 derived marker chromosomes, found in unrelated patients with dysmorphisms and/or developmental delay. Molecular cytogenetic analysis was performed using fluorescence in situ hybridization (FISH) with chromosome-specific painting probes, alpha satellite probes, and physically mapped probes from chromosome 13q, as well as comparative genomic hybridization (CGH). This analysis demonstrated that these markers consisted of inversion duplications of distal portions of chromosome 13q that have separated from the endogenous chromosome 13 centromere and contain no detectable alpha satellite DNA. The presence of a functional neocentromere on these marker chromosomes was confirmed by immunofluorescence with antibodies to centromere protein-C (CENP-C). The cytogenetic location of a neocentromere in band 13q32 was confirmed by simultaneous FISH with physically mapped YACs from 13q32 and immunofluorescence with anti-CENP-C. The addition of these three new cases brings the total number of described inv dup 13q neocentic chromosomes to 11, representing 21% (11/52) of the current overall total of 52 described cases of human neocentric chromosomes. This higher than expected frequency suggests that chromosome 13q may have an increased propensity for neocentromere formation. The clinical spectrum of all 11 cases is presented, representing a unique collection of polysomy for different portions of chromosome 13q without aneuploidies for additional chromosomal regions. The complexity and variability of the phenotypes seen in these patients does not support a simple reductionist view of phenotype/genotype correlation with polysomy for certain chromosomal regions.

Mammalian artificial chromosomes: modern day feats of engineering – Isambard Kingdom Brunel style

“…In addition, the DNA of the neocentromere supports the formation of a functional kinetochore with almost the correct complement of proteins. Kinetochore proteins CENP-A, CENP-C, CENP-E and CENP-I are found at neocentromeres, however CENP-B is not (Choo, 2001;Assumpcao et al, 2002;Li et al, 2002;Alonso et al, 2003;Craig et al, 2003;Amor et al, 2004). The formation of neocentromeres has been induced in the laboratory in Drosophila (Williams et al, 1998;Maggert and Karpen, 2001) and in a human and mouse hybrid somatic cell (Shen et al, 2001).…”

Origin of a Prenatal Mosaic Supernumerary Neocentromeric Derivative Chromosome 13 Determined by QF-PCR

“…The majority of neocentromeres represent inverted duplications of distal autosome regions, most commonly 15q25, 3q and 13q, and present as supernumerary marker chromosomes resulting in partial tri- or tetrasomy [4]. The clinical spectrum of phenotypes is variable and likely stems from the degree of duplication, mosaicism and tissue distribution of the supernumerary neocentromere chromosome [2]. There is only one report of prenatal detection of a supernumerary neocentromere chromosome 13 or neo(13) [5].…”

“…The second was an unbalanced, nonmosaic karyotype with 47 chromosomes consisting of a r(13)(pter→q14.1) and an inv dup(13)(q14→qter), resulting in trisomy for 13q14→qter [9]. The third case involves a mosaic supernumerary inv dup(13)(q14→qter), resulting in tetrasomy for 13q14→qter (case 2) [2]. The fourth case had a supernumerary neocentric 13q21→13q22 chromosome with a balancing reciprocal deletion [10].…”

“…The complexity and variability of the clinical phenotypes seen in patients with polysomy for 13q21→qter preclude any genotype-phenotype correlation due to the wide range of mosaicism [2]. The most frequent features observed in patients with partial trisomy/tetrasomy of 13q include facial dysmorphisms, hypotelorism, ear abnormalities and severe learning difficulties [12].…”

“…Centromeres, and the proteinaceous kinetochores that form there, are required for proper chromosome segregation during mitosis and meiosis. Neocentromeres are defined as a group of mitotically stable human derivative centromeres without alpha-satellite DNA that are able to form a primary constriction and participate in kinetochore formation [1,2,3]. Neocentromeres suggest that centromere formation is not solely dependent on alpha-satellite DNA, but on a distinct chromatin structure [4].…”