The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 189
have clinical findings associated with a partial monosomy. The specific phenotype of the individual
will depend on both the amount and the nature of the deleted material. Similarly, for a patient with a
supernumerary ring chromosome, the size of the ring, its genetic content, and the proportion of cells
that contain the ring will all influence phenotype.
Another phenomenon that has the potential to impact on the phenotype of individuals with ring
chromosomes is uniparental disomy (UPD) (see Chapter 19). Petersen et al. described a patient with
mosaicism for a normal cell line and a cell line in which one normal copy of chromosome 21 was
replaced by a ring (95). Uniparental isodisomy for chromosome 21 was present in the normal cell line.
The authors suggested that the isodisomy developed when the normal 21 was duplicated in a cell that
had lost the ring (“monosomy rescue”). Similarly, Crolla reported a patient with a supernumerary ring
6 in which the normal copies of chromosome 6 showed paternal isodisomy (96). Rothlisberger et al.
have reported a single case of mosaicism involving a cell line with a supernumerary ring derived from
chromosome 1 and a normal cell line with maternal uniparental heterodisomy for chromosome 1 (97).
The presence of uniparental heterodisomy (rather than isodisomy as described earlier) suggests that
both of the abnormal cell lines in this patient could have arisen secondary to trisomy rescue events (see
Chapter 19). Presumably, the original zygote had three copies of chromosome 1: one paternal chromosome
1 and two different maternal chromosome 1’s. Conversion of the paternal chromosome 1 into a
small ring would then produce a cell line with a survivable partial trisomy 1, rather than a lethal complete
trisomy. Subsequent loss of the ring chromosome would then ultimately produce a disomic cell
with the expected two copies of chromosome 1 and uniparental maternal heterodisomy for chromosome
1. Given that current data suggest there are no maternally imprinted genes on chromosome 1 that influence
phenotype, the resulting disomic cell line would be expected to demonstrate normal viability and,
perhaps, a selective growth advantage compared to the cell line with partial trisomy 1.
One recurring phenotype seen in ring chromosome heterozygotes is the “ring syndrome,” originally
proposed by Cote et al. in 1981 (98). These patients have 46 chromosomes, 1 of which is a ring
chromosome with no detectable deletion. The ring is derived from one of the larger chromosomes in
the karyotype, and the larger the chromosome, the more severe the phenotype. Typically, these
patients have severe growth retardation without major malformations. Minor anomalies and mild to
moderate mental retardation are often part of the picture. The ring syndrome is believed to result
from instability of the ring chromosome. The larger chromosomes are thought to be more unstable
than the smaller ones because they present more opportunities for sister chromatid exchange. The
breakage that occurs during cell division generates new ring structures, most of which represent a
more serious genetic imbalance than the previous forms and are, thus, less viable. This results in
increased cell death and contributes to growth failure and the disturbance of developmental pathways
(99). Kosztolanyi has proposed that this phenomenon might also contribute to the severity of the
phenotype in patients who have ring chromosomes with obvious deletions (99).
A 1991 literature review discovered 32 reported cases in which a ring chromosome was inherited
from a carrier parent. The authors concluded that no more than 1% of ring chromosomes are inherited.
Among the 32 patients with inherited rings, half had a phenotype similar to the carrier parent,
whereas approximately one-third were more severely affected (100). In over 90% of inherited ring
chromosome cases, the carrier parent is the mother (29).
In addition to the risks associated with ring instability, carriers of ring chromosomes might also be
at risk for having children with other abnormalities involving the chromosome from which their ring
is derived. There are at least three reports of carriers of a ring chromosome 21 who had offspring with
trisomy 21 secondary to a translocation or tandem duplication of chromosome 21 (100).
RECIPROCAL AUTOSOMAL TRANSLOCATIONS
Reciprocal translocations represent one of the most common structural rearrangements observed
in humans. Estimates of the population frequency range from 1/1000 to 1/673 (1,101). A reciprocal