A Series of supernumerary small ring marker autosomes identified by FISH with chromosome probe arrays and literature review excluding chromosome 15

Abstract

Seven supernumerary small ring marker autosomes were studied. The pantelomere probe (Oncor) in conjunction with scoring for dicentric rings was used to confirm ring morphology. The small rings were identified mainly by FISH with chromosome probe arrays (Cytocell) containing representations from all 24 chromosomes and the rings were derived from chromosomes 7, 8 (three cases), 11, 12, and 14. The effectiveness of the array methodology in identifying markers was tested. Microsatellite DNA data showed biparental disomy (BPD) was present for the rings from chromosomes 7 and 14 thereby excluding UPD, both were de novo but the ring 14 was of paternal origin. The literature on supernumerary small ring autosomes was reviewed excluding chromosome 15. The grade and distribution of mosaicism was invoked as the major determinant of the differences in phenotype and, in addition, variation was attributed to the possibility of different contributions from each chromosome arm. There are 88 published supernumerary small ring cases in total, with phenotypic data attributable to the respective rings in 77 cases and all chromosomes being represented except chromosome 17. Of the prenatally ascertained cases, where there was adequate phenotypic data, 30% had an abnormal phenotype attributable to the ring, and there were 44% familial cases in this group. Of the postnatally ascertained small rings, 75% had an abnormal phenotype attributable to the ring and there were 13% familial cases. This higher abnormality rate is concordant with the considerable ascertainment bias of this latter group and the prenatal data are recommended for genetic counseling. Although data are small there were some differences between the rings derived from different chromosomes. Chromosomes 3 and 8 demonstrate the extremes. Of the supernumerary small r(8) cases reviewed including the three presently described, 8/11 had an abnormal phenotype attributable to the marker but of the small r(3) cases, only 1/6 had an abnormal phenotype. Two of the present r(8) were studied with the GATA4 probe at 8p23.1. The r(8) in case 2 (patient moderately retarded) was comprised mostly of an intact 8p whereas the larger r(8) in case 3 (normal phenotype) was missing 8p23.1 --> pter and had more of 8q contributing to the ring. In other supernumerary rings postnatally ascertained, there is mostly insufficient data but there is an abnormal phenotype in 8/11 cases with multiple small rings, in 5/6 cases with r(20), and in 5/10 with r(1). A novel origin for supernumerary small rings is proposed: that they may originate from incompletely digested superfluous (haploid) pronuclei. The small rings presumptively so formed may occasionally be transfected into the zygote nucleus. The high proportion ( approximately 12.5%) of cases with multiple supernumerary small rings almost always of different centromeric origin is consistent with this concept.

Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: Cooperative study of 19 Italian laboratories

“…[17][18][19] The use of PACs/BACs and the evolution of FISH techniques (reverse painting and CGH), CGH microarray, and so forth have made it possible to "size" sSMCs and define their content very finely. However, the literature contains few descriptions of sSMCs grouped by marker type from which karyotype-phenotype correlations can be deduced to allow correct genetic counseling.…”

“…Starke et al 20 provided a first step toward the identification of pericentromeric diseaserelated genes by showing that only a few proximal trisomies underlie clinical manifestations. The phenotypic variability associated with sSMCs originating from the same chromosome may reflect the degree of mosaicism, 17,19 the UPD status of the originating chromosome pair, the DNA sequence content (repeated vs. coding DNA), and the size in terms of the multiplicities of genes and/or imprinted regions involved. As in the case of contiguous gene syndromes, in which one or a few genes may be responsible for disease, [21][22][23] the presence or absence of a specific genomic fragment can determine a normal/mild/ severe phenotype, even if the sSMCs comes from the same chromosome.…”

Prenatal Diagnosis of Minute Supernumerary Marker Chromosomes

“…Cytogenetic analysis of amniocytes showed a male karyotype with mosaicism for a minSMC: mos47,XY,+mar [27]/46,XY [23] ( fi g. 1 -3A). CBG-banding showed the minSMC to be only partially heterochromatic ( fi g. 1 -3B).…”

Retained heterodisomy for chromosome 12 in atypical lipomatous tumors: implications for ring chromosome formation

“…The preferential involvement of chromosome 12 would then be the result of selection. A similar scenario has recently also been suggested for the origin of constitutional supernumerary ring chromosomes, with incompletely digested pronuclei serving as the source for the additional chromosome material (Daniel and Malafiej, 2003). …”