Human Ring Chromosomes - New Insights for their Clinical Significance.

Twenty-nine as yet unreported ring chromosomes were characterized in detail by cytogenetic and molecular techniques. For FISH (fluorescence in situ hybridization) previously published high resolution approaches such as multicolor banding (MCB), subcentromere-specific multi-color-FISH (cenM-FISH) and two to three-color-FISH applying locus-specific probes were used. Overall, ring chromosome derived from chromosomes 4 (one case), 10 (one case), 13 (five cases), 14, (three cases), 18 (two cases), 21 (eight cases), 22 (three cases), X (five cases) and Y (one case) were studied. Eight cases were detected prenatally, eight due developmental delay and dysmorphic signs, and nine in connection with infertility and/or Turner syndrome. In general, this report together with data from the literature, supports the idea that ring chromosome patients fall into two groups: group one with (severe) clinical signs and symptoms due to the ring chromosome and group two with no obvious clinical problems apart from infertility.

Five novel locations of Neocentromeres in human: 18q22.1, Xq27.1∼27.2, Acro p13, Acro p12, and heterochromatin of unknown origin.

Since the first report in 1993, an ectopic centromere, i.e. neocentromere formation, has been reported in more than 100 small supernumerary marker chromosomes (sSMC), in 7 instances of centromere repositioning, and in about a dozen cases with more complex chromosomal rearrangements. Here we report 2 new cases with centromere repositioning and 3 neocentric sSMC consisting exclusively of heterochromatic material. Yet, no centromere formation was reported for the regions 18q22.1 and Xq27.1∼27.2 as it was observed in the 2 cases with centromere repositioning here; in both cases, cytogenetically an inversion was suggested. Two of the 3 neocentric sSMC were derived from a short arm of an acrocentric chromosome. The remainder neocentric sSMC case was previously reported and was stainable only by material derived from itself.

Molecular cytogenetic characterization of two cases with de novo small mosaic supernumerary marker chromosomes derived from chromosome 16: towards a genotype/phenotype correlation.

Small supernumerary marker chromosomes (sSMC) derived from chromosome 16 are rare and, so far, it is not yet clear which regions of chromosome 16 are critical and have clinical consequences. We have characterized two cases with a ring-shaped sSMC derived from chromosome 16. In case A the sSMC was encountered prenatally and was characterized using centromeric fluorescence in situ hybridization (FISH) probes, subcentromere-specific multicolor FISH (subcenM-FISH), reverse FISH and array-CGH, using a full-tiling BAC array specific for chromosome 16. Case B is a postnatal case and the sSMC was characterized by centromeric FISH probes and subcenM-FISH. Our results, using molecular cytogenetics, showed that both sSMC were derived from chromosome 16, resulting in a de novo mosaic partial trisomy of chromosome 16, involving euchromatic material from 16q. Array painting, in case A, allowed the localization of the sSMC breakpoints, revealing that the sSMC comprised the 33.43-47.02 Mb region of chromosome 16 (16p11.2 to 16q12.1), a region known to harbor some protein-coding genes. In general, the phenotypic consequences of a de novo marker chromosome are difficult to assess. Molecular cytogenetics techniques are a valuable tool for the accurate identification of the origin and content of marker chromosomes, contributing to a more informed prenatal counseling and patient follow-up. Besides multicolor FISH approaches, array painting, combining microdissection and array-CGH, is very useful for mapping size and breakpoints of marker chromosomes, since sSMC are often only present in a small percentage of cells.

Forty-eight new cases with infertility due to balanced chromosomal rearrangements: detailed molecular cytogenetic analysis of the 90 involved breakpoints.

A molecular cytogenetic study was performed on 48 infertile patients who were identified as carriers of balanced translocations (40 cases), inversions (6 cases) or insertions (2 cases) by means of banding cytogenetics. Cases with a Robertsonian translocation or pericentric inversion 2 or 9 were not included. In summary, 100 break-events occurred in these patients, and 90 different chromosomal regions were involved. Thus, this study confirmed the presence of abnormal karyotypes in a subgroup of patients seeking infertility treatment. Breaks were demonstrated to appear preferentially in GTG-light bands in these patients. Furthermore, the observed breakpoints were associated with genomic regions prone to instability due to the presence of segmental duplications. Nonetheless, further detailed molecular analysis will be necessary in the future to characterize the mechanisms and genetic basis for this phenomenon.

Small supernumerary marker chromosomes--progress towards a genotype-phenotype correlation.

Small supernumerary marker chromosomes (sSMC) are still a major problem in clinical cytogenetics as they are too small to be characterized for their chromosomal origin by traditional banding techniques, but require molecular cytogenetic techniques for their identification. Apart from the correlation of about one third of the sSMC cases with a specific clinical picture, i.e. the i(18p), der(22), i(12p) (Pallister Killian syndrome) and inv dup(22) (cat-eye) syndromes, most of the remaining sSMC have not yet been correlated with clinical syndromes. Recently, we reviewed the available >1600 sSMC cases (Liehr T, sSMC homepage: http://mti-n.mti.uni-jena.de/~huwww/MOL_ZYTO/sSMC.htm). A total of 387 cases (including the 45 new cases reported here) have been molecularly cytogenetically characterized with regard to their chromosomal origin, the presence of euchromatin, heterochromatin and satellite material. Based on analysis of these cases we present the first draft of a basic genotype-phenotype correlation for sSMC for all human chromosomes apart from the chromosomes Y, 10, 11 and 13.

Duplications of proximal 16q flanked by heterochromatin are not euchromatic variants and show no evidence of heterochromatic position effect.

Extra euchromatic material was found within the major heterochromatic block of chromosome 16 (16qh) in one de novo case and seven members of two families. In contrast to the euchromatic variants of chromosome 9 (9qh), which are derived from pericentromeric euchromatin, molecular cytogenetics confirmed that these duplications were of 16q11.2-->q12.2 in the de novo case, of 16q11.2-->q13 in three members of family 1 and 16q11.2-->q12.1 in four members of family 2. The duplication had arisen as a post-zygotic mitotic event in the mother of family 1 and been transmitted paternally in family 2. An insertional mechanism of origin is proposed for the duplications in case 1 and family 1. Expression at the 16q13 matrix metalloproteinase-2 (MMP2)locus in families 1 and 2 was proportional to genomic copy number and not therefore consistent with position effect silencing due to the flanking blocks of heterochromatin. We conclude that proximal 16q duplications within 16qh are not novel euchromatic variants but associated with a variable phenotype including developmental delay, speech delay, learning difficulties and behavioural problems. The behavioural problems in families ascertained through affected children are much less severe than those encountered in previous patients ascertained as adults.

Three cases with rare interstitial rearrangements of chromosome 1 characterized by multicolor banding.

In this report, we describe three unrelated patients with similar symptoms such as mental retardation, growth delay and multiple phenotypic abnormalities. GTG-banding analysis revealed karyotypes with add(1p) in two cases and an add(1q) in the third. Fluorescence in situ hybridization (FISH) analysis using high resolution multicolor banding (MCB) characterized the aberrations of the abnormal chromosomes 1 as a (sub)terminal duplication and inverted duplications, respectively. Although three different chromosomal regions i.e. 1p36.1, 1p36.2-->1p31.3 and 1q41-->1q44 were involved, all three patients had similar patterns of dysmorphic findings. These cases demonstrate the power of MCB in the characterization of small interstitial chromosomal aberrations and resulted in the characterization of three previously unreported congenital chromosome 1 rearrangements.

Small supernumerary marker chromosomes (sSMC) in patients with a 45,X/46,X,+mar karyotype - 17 new cases and a review of the literature.

Small supernumerary marker chromosomes (sSMC) can appear in a numerically normal 'basic karyotype', but also in a numerically abnormal one like a Turner syndrome karyotype (= sSMC(T)). Here we present 17 new cases with such a mos 45,X/46,X,+mar karyotype. Moreover we reviewed all 512 cytogenetically similar cases available from the literature and supply for the first time data on occurrence, shapes and subgroups of this rare cytogenetic entity. sSMC(T) are very rare in the common population (1:100,000) - however, they can be observed with a 45- and even 60-times higher frequency in infertile and (develop)mentally retarded patients, respectively. Even though sSMC(T) derive from one of the gonosomes in >99% of the cases, there are also exceptional reports on sSMC(T) derived from one of the autosomes. The majority of sSMC(T)(X) form ring chromosomes, while most sSMC(T)(Y) are inverted duplicated/isodicentric chromosomes. Although >500 sSMC(T) are reported, a detailed characterization of the chromosomal breakpoints is only given for a minority. Thus, more cases with detailed (molecular) cytogenetic marker chromosome characterization are needed to provide information on formation and effects of an sSMC(T).