HUMAN RING CHROMOSOMES – NEW INSIGHTS
FOR THEIR CLINICAL SIGNIFICANCE Guilherme RS1,2, Klein E1, Hamid AB1, Bhatt S1, Volleth M3, Polityko A4, Kulpanovich
A5, Dufke A6, Albrecht B7, Morlot S8, Brecevic L9, Petersen MB10, Manolakos E10,
Kosyakova N1, Liehr T1* *Corresponding Author: Thomas Liehr, Institut für Humangenetik, Kollegiengasse 10, Postfach D-07740
Jena, Germany; Tel.: +49-3641-935533; Fax: +49-3641-935582; E-mail: i8lith@mti.uni-jena.de page: 13
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RESULTS AND DISCUSSION
In 29 cases with ring chromosomes, the chromosomal
origin and content could be determined
using molecular cytogenetics. The rings were derived
from chromosome 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). The exact breakpoints and mosaic states
are summarized in Table 1 and examples of the
FISH results are shown in Figure 1. In the following
data, the obtained results were compared with
the literature by chromosomal origin; afterwards,
the chromosomal imbalances were analyzed, and
finally, a conclusion was drawn.
Analyzed Rings by Chromosomal Origin.
Numerous cases for ring chromosomes 4 have been
reported previously [12-14]. Interestingly, those
cases fall into two cytogenetic groups: one group
where the ring is stable and the other group where it
is unstable within the studied cells, as in case R-1.
Further studies are necessary to rule out where this
instability comes from, and what the clinical impact
is. To the best of our knowledge, no clinically normal
ring chromosome 4 case has yet been reported.
In case R-2, the first ever seen balanced ring formation
involving chromosome 10 formed by the Mc-
Clintock mechanism [2] is reported. The rearrangement
was connected with clinical problems, as the
ring was lost in ~20.0% of the cells. Ring chromosomes derived from chromosome 10 are rare (only
about 10 cases) and were recently reviewed [15].
Martin et al. [16] suggested the existence of
a ring chromosome 13 syndrome and gave an incidence
of 1/58,000 in live births. Here, five cases
with ring chromosomes 13 were studied (R-3 to R7),
all of them were clinically abnormal.
Similarly to chromosome 13 derived rings,
chromosome 14 is also suggested as a specific syndrome
[17]. In concordance with the literature, all
three ring chromosome 14 cases studied here (R-8 to
R10) had an abnormal pheno-type.
Ring chromosomes 18 were present in the prenatally
studied cases R-11 and R-12. Here too, a recognizable
syndrome was suggested [18]. Similar to
chromosome 4, for rings derived from chromosome
18, cytogenetically stable (e.g., present two cases)
and unstable rings [19] are reported.
Eight cases with ring chromosomes 21 were
char-acterized in the present study (cases R-13 to
R-20). While cases R-13 to R-15 were unbalanced
and led to clinical signs, two of the cases just detected
were due to infertility (R-17 and R-20). As
reported in [20], most, if not all ring chromosome 21
cases are mosaic, as the ones here described. A ring
chromosome 21 syndrome was also postulated [21].
The three ring chromosome 22 cases were either
cyto-genetically stable (R-21 and R-22) or unstable
(R-23). The reason for the cytogenetic study
was available only for case R-21; it was infertility,
and in the literature there are several similar cases
reported [22].
Turner syndrome is cytogenetically characterized
by karyotype 45,X; in ~5.0% of the cases, this
main cell line is accompanied by a second one having
46 chromosomes due to an additional derivative
X- or Y-chromosome [23]. Here, six such cases were
characterized in more detail, as they had a ring derived
from the X-chromosome (cases R-24 to R-28)
or the Y-chromosome (R-29). Interestingly, all cases
were detected during adulthood and only two of
them due to a suspicion of Turner syndrome (R-24
and R-26). The majority of the cases were referred
due to infertility.
Ring Chromosome-Induced Imbalances. In
all 29 studied ring chromosome cases (Table 1), euchromatic
imbalances were present except for cases
R-7, R-21 and R-22. In the latter, clinical data was
available only for case R-21, and infertility was the
only clinical problem observed there. Primarily, case
R-2 did not have any imbalance due to a ring chromosome,
but double ring formation and loss of the
ring chromosome led to a partial tri - or monosomy
in 23.0% of the patient’s cells overall.
Imbalances were exclusively induced by the
ring chromosome formation in case R-10. Moreover,
in all the remaining 24 cases, imbalances were also
caused by sec-ondary effects of the ring chromosome
formation: i) double ring formation: R-1, R-3 to R-5,
R-8, R-15, R-16, R-18 to R-20, R-23, R-28 and
R-29; ii) ring doubling: R-1, R-15, R-26 and R-28;
iii) complex changes of the ring itself: R-1, R-15 to
R-17 and R-23; iv) ring opening (including further
rearrangements): R-1, R-8, R-11, R-13, R-15, R-17,
R-19, R-20 and R-23; v) loss of the ring: R-1, R-4,
R-6, R-8, R-9, R-12 to R-16, R-19 and R-24 to R-29.
Similar observations were also made for other
ring chromosomes 22. The idea that there might even
be a “ring syndrome” irrespective of the chromosomal
origin of the ring [24] might be due to the gross imbalances
induced by these secondary changes [25].
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