Mosaic inv dup(8p) marker chromosome with stable neocentromere suggests neocentromerization is a post-zygotic event

Abstract

Marker chromosomes containing active human neocentromeres have been described in individuals where the chromosomes are non-mosaic, suggesting that they are mitotically stable, but also in individuals where there is mosaicism, raising the possibility of neocentromere instability. We report two independently ascertained individuals who are mosaic for a supernumerary marker chromosome, shown by reverse chromosome painting to have an 8p origin, resulting in mosaicism for tetrasomy 8p23.1-->pter in the patient. The markers have a primary constriction but show no detectable centromeric alpha-satellite DNA. The marker in Patient 1 demonstrated no centromere protein CENP-B binding, but associated with nine different functionally critical centromere proteins. Investigation of peripheral blood lymphocytes from this patient on five separate occasions over a 13-year period showed 23-46% mosaicism for the marker chromosome with no decrease in incidence. In vitro investigation of primary and secondary sub-clones of a lymphoblast cell line derived from the patient demonstrated 100% stability of the marker chromosome indicating that neocentromere instability is unlikely to be responsible for the mosaicism in the patient. This and other available data support a general model of neocentromerization as a post-zygotic event, irrespective of whether the supernumerary chromosome fragment has arisen during meiosis or post-fertilization at mitosis.

Class II neocentromeres: a putative common neocentromere site in band 4q21.2

“…4 The possibility of disruption of fetal development due to an early cell line monosomic for most of chromosome 4, subsequently selected against and lost, cannot therefore be excluded. This is the second report of neocentromere formation in band 4q21 and thus refines a putative neocentromeric site to sub-band 4q21.2.…”

“…10 These have been termed class I type neocentromere analphoid chromosomes. 4 Only nine neocentromeres have been documented on acentric fragments derived from interstitial deletion events (termed class II type analphoid chromosomes). The deletion is followed by fusion of the two more distal chromosome fragments and thus theoretically results in a balanced karyotype.…”

“…The mitotic stability of neocentromeres is well documented. 4 Moreover, recent cases have reported the inheritance of 'neocentromeric' chromosomes suggesting that they also have the capacity to function successfully during meiosis. 3,5 Neocentromeres are usually devoid of a-satellite DNA.…”

Neocentric X-chromosome in a girl with Turner-like syndrome

“…The novel position of CENP-C and absence of alpha satellite DNA in the abnormal X chromosome defined a neocentromere, which also explains its mitotic stability. The mosaicism observed in the karyotype of our patient is very likely a consequence of gradual formation, stabilization, and functioning of the neocentromere after several post-fertilization cell divisions, during which the iso(Xq) may be lost in a proportion of cells [14,26]. …”

“…Alternatively, mosaicism could arise from a meiotically derived marker if neocentromere function was not established at the time of meiotic rearrangement. In this scenario, neocentric function would develop after several post-fertilization cell divisions, during which some of the markers would be lost [14]. …”